The excipient news blog - shared with the Linkedin pharma excipients group! Pharmaceutical excipients (inactive ingredients) play a major role in development and production of pharmaceutical dosage forms - we publish up to date information on all aspects of excipients.

Excipienttalk - Latest news on pharmaceutical excipients

Ammonio methacrylate copolymer as a carrier for water-insoluble drug, preparation and characterization of an oral controlled-release matrix tablet

Abstract

The use of ammonia methacrylate copolymer as a carrier for the preparation of oral controlled-release matrix tablets containing water-insoluble drugs and investigating the effect of curing conditions. Tablets were cured at 40 °C with or without 75% relative humidity (RH). The crystalline structures were analyzed with powder X-ray diffractometry and dissolution studies were performed in USP dissolution apparatus type II. With increasing the ethanol content (0–20%, w/w) in the granulation fluid, the drug release was decreased. The drug release from the tablets cured at 70 °C/24 h was similar to those that cured at 40 °C with 75% RH/24 and the drug release kinetic was fitted with the zero-order release mechanism. The x-ray study showed no change in the crystalline structure of carbamazepine. As the curing duration, compression force and granule size were increased, the drug release was decreased. The drug release was proportionally changed with surface area/volume ratio, agitation rate, and polymer permeability; meanwhile, the release was unchanged with increased drug content from 30% to 50% w/w. Ammonio methacrylate copolymer could be used as a carrier for water-insoluble drugs and to prepare controlled-release matrix tablets.

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Effect of amphiphilic graft co-polymer-carrier on physical stability of bosentan nanocomposite: Assessment of solubility, dissolution and bioavailability

Abstract

Bosentan is a dual endothelin receptor antagonist used in the treatment of pulmonary arterial hypertension (PAH). But the solubility and bioavailability of this drug are poor, which has restricted the design and development of dosage forms for efficient and successful therapy. The present study was carried out to develop nanocomposites using an amphiphilic graft co-polymer (Soluplus®) as a carrier to enhance the solubility and bioavailability of bosentan. The graft co-polymer-based nanocomposite formulation was prepared using the single-emulsion technique. The nanocomposite was characterised in terms of particle size analysis, solubility, percentage entrapment efficiency, drug-loading capacity, surface morphology, drug content, in vitro dissolution, stability and bioavailability. FT-IR study revealed that there was no interaction between the drug and Soluplus®. DSC analysis of the nanocomposite formulation confirmed that the bosentan was completely encapsulated within a Soluplus®. XRD analysis showed that the drug was converted to an amorphous form irreversibly. SEM images showed that the particles were of size 96-129 µm and had slightly smooth to rough textured surface. TEM analysis indicated that the diameters of the prepared bosentan nanocomposite after dispersion in distilled water were 13.69–96.78 nm. Statistically significant increases in the solubility, dissolution and bioavailability of the drug were observed. It was confirmed that the use of a graft co-polymer carrier-based nanocomposite formulation is a good approach for efficient delivery of bosentan, the solubility and bioavailability being increased manifold.

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Macromolecular confinement of therapeutic protein in polymeric particles for controlled release: insulin as a case study

ABSTRACT

Sustained release systems for therapeutic proteins have been widely studied targeting to improve the action of these drugs. Molecular entrapping of proteins is particularly challenging due to their conformational instability. We have developed a micro-structured poly-epsilon-caprolactone (PCL) particle system loaded with human insulin using a simple double-emulsion w/o/w method followed by solvent evaporation method. This formulation is comprised by spheric-shaped microparticles with average size of 10 micrometers. In vitro release showed a biphasic behavior such as a rapid release with about 50% of drug delivered within 2 hours and a sustained phase for up to 48 h. The subcutaneous administration of microencapsulated insulin showed a biphasic effect on glycemia in streptozotocin-induced diabetic mice, compatible with short and intermediate-acting behaviors, with first transition peak at about 2 h and the second phase exerting effect for up to 48h after s.c. administration. This study reveals that a simplified double-emulsion system results in biocompatible human-insulin-loaded PCL microparticles that might be used for further development of optimized sustained release formulations of insulin to be used in the restoration of hormonal Levels.

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Biosimilar and Interchangeable Biologics: What Is What?

For decades, everybody has become familiar with many brand-name and generic chemically synthesized drugs that are small molecule drug products, such as amoxicillin, Lipitor, and Crestor. Biological products, on the other hand, are practically and conceptually different as a class of therapeutic medicinal products. Biological products may be broadly considered inclusive of vaccines, blood components, or proteins (unless chemically synthesized polypeptides), as well as other defined products. Currently in the United States, a number of biological products have been approved for prevention of diseases (e.g., vaccines), for treatment of autoimmune diseases (e.g., arthritis, psoriasis), and for treatment of cancer (e.g., non-Hodgkin lymphoma, some types of colorectal cancer).

 

As the proliferation of biologic products continues, so will the proliferation of biosimilar products with respect to innovator products, also known as the reference biologic product (RBP) to which a biosimilar is compared. Consequent to the expanded development and approval of biosimilars will be determining whether a biosimilar product is interchangeable with, and can be used in lieu of, an RBP.

From AAPS Blog by BY LOAN PHAM AND VIEN LAI 

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ICH M9: Biopharmaceutics Classification System Biowaivers

Introduction

The International Conference on Harmonization (ICH) M9: Biopharmaceutics Classification System-based Biowaivers,1,2 was adopted in mid-June 2016. A biowaiver allows for in vitro testing to be used in lieu of in vivo bioavailability and/or bioequivalence studies to facilitate product approval, where solubility and permeability are not expected to impede bioavailability. ICH M9 will therefore minimize unnecessary in vivo studies in man and allow greater public access to vital medicines. However, this approach is not always universally aligned or recognized.

The Role of Biowaivers

In certain cases regulatory applications using biowaivers are permissible. Submissions can be either based on BCS, in vitro - in vivo correlation (IVIVC), in vitro - in vivo relationship (IVIVR) or simply on an in vitro dissolution profile comparison. Examples of the BCS, IVIVC or IVIVR biowaiver approach include:

  • in support of generic product entry versus the innovator product
  • in support of regulatory submission, i.e. changing the product type during development (capsules to tablets, etc.)
  • in support of over-encapsulated comparator products, that are often used in pivotal clinical studies
  • in support of bridging between the product used in pivotal clinical studies and the ‘to be marketed’ commercial product
  • in support of product line extensions (PLEs) for different clinical populations, i.e. pediatric or geriatric products
  • in support of post-approval changes

History and Evolution of BCS

The BCS was introduced in 19954 to facilitate the introduction of biowaivers into the regulatory lexicon. The BCS scheme is a 4-box model for drug product assessment based on an evaluation of the drug solubility and permeability. There are four classifications: BCS class 1 (highly soluble and highly permeable), class 2 (poorly soluble and highly permeable), BCS class 3 (highly soluble and poorly permeable) and BCS class 4 (poorly soluble and poorly permeable).

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Oral Disintegrating Tablets:Background and Review on Recent Advancements

Most of the drug products available in the market are for oral drug administration. Oral route is preferred due to ease of administration, versatility, patient compliance and accurate dosing. However, oral administration is not suitable for people with dysphasia, a condition that results in difficulty in swallowing. Also, for many geriatric and pediatric patients, oral administration might not be a preferred route. In this regards, oral disintegrating tablets (ODT) provide a useful alternative. When ODT comes in contact with saliva, these tablets disintegrate instantaneously (within 30 sec) resulting in the release of drug. Furthermore, since it undergoes pre-gastric absorption, it bypasses first pass metabolism, which can be beneficial for drugs with significant hepatic metabolism. This review article discusses the traditional and advanced technologies utilized in manufacturing of ODT, excipient selection and quality control test. The article also discusses its application in various disease conditions.

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Nanostructured lipid carriers as oral delivery systems for poorly soluble drugs

Abstract

Poorly water soluble (PWS) drugs lack from good oral absorption, which limits their oral administration, the most common drug delivery route. The design of appropriate innovative formulations for PWS drugs will allow for adequate bioavailability, reduction of the required dose and oral delivery of drugs that would otherwise need the parenteral route. Among the formulations under study, Nanostructured Lipid Carriers (NLCs), made of biocompatible mixtures of solid and liquid lipids, represent a good choice. NLCs enhance the apparent solubility and dissolution of PWS drugs in the gastrointestinal tract, and/or modulate the drug permeability and fate across the intestinal barrier, opening new perspectives in the field of innovative medicines for oral administration of PWS molecules. Recently, NLCs have also emerged as a promising anti-inflammatory drug delivery system for inflammatory bowel diseases. The present paper is focused on the state of the art of NLCs for oral delivery of PWS drugs. The design, the main preparation techniques and the mechanisms through the drug oral delivery is improved by NLCs are presented, highlighting the influence of the most relevant technological and formulation factors on the properties of the NLCs, which condition their efficacy as oral delivery formulations.

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Taste-masking assessment of orally disintegrating tablets and lyophilisates with cetirizine dihydrochloride microparticles

Abstract

Orally disintegrating tablets and oral lyophilisates are novel attractive dosage forms that disintegrate or dissolve in the buccal cavity within seconds without necessity of drinking. The major limitation in designing of these dosage forms is unpleasant taste of the drug substance. Cetirizine dihydrochloride is a H1-antihistamine substance indicated for the treatment of allergy. It is characterized by extremely bitter taste, therefore in order to deliver cetirizine dihydrochloride using orodispersible formulations, effective taste-masking is required. The aim of this study was to investigate whether microparticles containing cetirizine dihydrochloride could be successfully used to formulate orally disintegrating tablets by direct compression method and oral lyophilisates by freeze-drying process. Taste masking of cetirizine dihydrochloride was achieved by the spray-drying technique using Eudragit® E PO as the drug agent carrier. Based on the preliminary studies, optimal compositions of microparticles, tablets and lyophilisates were chosen. Obtained dosage forms were characterized for drug content, disintegration time and mechanical properties. In order to determine whether the microparticles subjected to direct compression and freeze-drying process effectively mask the bitter taste of cetirizine dihydrochloride, the in vivo and in vitro evaluation was performed. The results showed that designed formulates with microparticles containing cetirizine dihydrochloride were characterized by appropriate mechanical properties, uniformity of weight and thickness, short disintegration time, and the uniform content of the drug substance. Taste-masking assessment performed by three independent methods (e-tongue evaluation, human test panel and the in vitro drug release) revealed that microparticles with Eudragit® E PO are effective taste – masking carriers of cetirizine dihydrochloride and might be used to formulate orally disintegrating tablets and oral lyophilisates.

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Retrospective Quality by Design (rQbD) applied to the optimization of orodispersible films

Abstract

The study demonstrates the application of QbD based on historical data for a product at a later development stage – retrospective QbD (rQbD). More specifically, it is investigated the root-cause for the observed slower drug release in Orodispersible Films (ODFs) during storage. Risk assessment tools were used to identify parameters affecting ODFs critical quality attributes, namely percent drug release and residual water content. The parameters room temperature, room relative humidity, drying temperature and mixing equipment were used in the statistical modeling of the available data. The estimated models were then used to define the feasible working region. Statistical modeling indicates that initial residual water content of the ODFs is mainly affected by 2nd order interactions of room temperature, room relative humidity and drying temperature, while the stability of drug release profile is mostly influenced by room temperature and an interaction between room relative humidity and drying temperature. Depending on the drying temperature employed the effect of room temperature and room relative humidity change significantly. This work shows that it is possible to apply rQbD to achieve a greater understanding of the manufacturing process of ODFs and to define a proper design space.

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Mesoporous silica-based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate

Objectives

Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed.

Key findings

Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 ± 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 ± 14.58% as a suspension, compared to 19.92 ± 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency.

Conclusions

The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation.

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A Quality by Design Approach for Coating Process Parameter Optimization

Film coating is a thin polymer layer applied on to a solid dosage form. Quality by design approach was explored to optimize the tablet coating process using Opadry®, an optimized one step film coating system. A central composite design was chosen by considering independent variables as inlet temperature, atomization air pressure, spray rate and dependent variables as weight gain and tablet surface roughness. Non-linear regression models were developed for response variables. The model was used to achieve an optimized response characteristic of weight gain, surface roughness with predicted input variables of inlet air temperature, atomization air pressure and spray rate. With optimized process parameters tablet has been coated and the suitability of the model determined. The results demonstrated the overall reliability and effectiveness of the proposed quality by design approach to the derived model and provides useful tool to help optimize the film coating process.

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Artificial Intelligence: The Future of Pharma

In the past, machines were considered as tools that reduce human effort by performing tasks that humans are capable of, except thinking and learning. Machines, these days, come with cognitive skills as well, making them highly intelligent, if not to the level of humans. Artificial intelligence (AI) is currently being utilized in a variety of areas including self-driving cars and interpreting complex data. The former have the ability to maneuver in heavy traffic, react instantaneously to unpredictable pedestrians or drivers, and face a completely new environment on-road every time, all of which is possible because of the complex algorithm built into it for learning, a term called  machine learning. Machine learning has also made machine-mediated interpretation of complex data a reality.

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Application of surfactants in solid dispersion technology for improving solubility of poorly water soluble drugs

Abstract

Discovery of several poorly water soluble drugs in the past decade has led to the need of developing a novel dosage form which increases the solubility of the drug and improves oral bioavailability. Solid dispersion is one of the most promising techniques to overcome the challenges faced by poor water solubility. However, there are several limitations associated with the development of solid dispersion, like miscibility of polymer and drug, the stability of the dispersion, etc. The use of surfactant in the solid dispersion can overcome these limitations. The addition of surfactant to solid dispersion not only increases drug-polymer miscibility but also reduces recrystallization. It also improves the wettability of solid dispersion, which leads to increase in dissolution and physical stability. However, caution must be employed in selecting the surfactant. The surfactant can interact with polymer and thereby increase the recrystallization of drugs. This review focuses on the use of surfactant in the solid dispersion. First, the classification of the surfactant is discussed along with its use in the formation of solid dispersion by various techniques.

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What does the future hold for pharmaceutical excipients?

Many of the excipients we use today have been around for more than fifty years. In many cases, the specifications for those excipients have not changed much over the years, either. During that time, we have not really thought about what happens when our existing excipients, and/or their specifications, are no longer able to provide us with the necessary performance to allow effective medicines to be

formulated, developed and manufactured on a routine basis. Things are changing!

 

We have moved into a new era. With the advent of combinatorial chemistry,

high-throughput screening, recombinant technologies and better understanding of

proteins, drug-receptor interactions, monoclonal antibodies, and the like, today we

have very sophisticated tools which help us to discover very effective drugs we could hardly imagine fifty years ago. However, innovation in excipients has not kept pace with the advances in drug discovery.

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Sulfadiazine-based drug delivery systems prepared by an effective sol–gel process

Abstract

In the present contribution a versatile and sustainable strategy for the formulation of a drug delivery system for the controlled release of antibiotics for topical administration was developed. Silver sulfadiazine (AgSD), an antimicrobial agent for preventing infections on burn wounds, was selected as model drug. The drug delivery system was formulated by an effective one-pot sol–gel approach by using chitosan and silica alkoxides as organic and inorganic precursor, respectively, in order to obtain a hybrid material. Different silica alkoxides, characterized by different functionalities of the organic chain, and a series of synthetic parameters (water/precursor ratio, excipients, and drug amount) were evaluated. The composition of the hybrid gel was selected to achieve the optimal synergy between the physico-chemical features and the gel texture taking into great account the final application, i.e., a topical administration. Drug delivery tests were performed in vitro with a Franz vertical diffusion cell. The new drug delivery system reaches the therapeutic concentration in the same time of a commercial sample and allows the complete release of even 2.5 wt% AgSD. The drug delivery is totally controlled and gradual over 48 h and the formulated is stable in time. Such innovative organic–inorganic hybrid material is therefore an efficient drug delivery system for acute skin infections treatment by controlled delivery.

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An investigation into the effects of excipient particle size, blending techniques and processing parameters on the homogeneity and content uniformity of a blend

Powder blend homogeneity is a critical attribute in formulation development of low dose and potent active pharmaceutical ingredients (API) yet a complex process with multiple contributing factors. Excipient characteristics play key role in efficient blending process and final product quality. In this work the effect of excipient type and properties, blending technique and processing time on content uniformity was investigated. Powder characteristics for three commonly used excipients (starch, pregelatinised starch and microcrystalline cellulose) were initially explored using laser diffraction particle size analyser, angle of repose for flowability, followed by thorough evaluations of surface topography employing scanning electron microscopy and interferometry. Blend homogeneity was evaluated based on content uniformity analysis of the model API, ergocalciferol, using a validated analytical technique. Flowability of powders were directly related to particle size and shape, while surface topography results revealed the relationship between surface roughness and ability of excipient with high surface roughness to lodge fine API particles within surface groves resulting in superior uniformity of content. Of the two blending techniques, geometric blending confirmed the ability to produce homogeneous blends at low dilution when processed for longer durations, whereas manual ordered blending failed to achieve compendial requirement for content uniformity despite mixing for 32 minutes. Employing the novel dry powder hybrid mixer device, developed at Aston University laboratory, results revealed the superiority of the device and enabled the production of homogenous blend irrespective of excipient type and particle size. Lower dilutions of the API (1% and 0.5% w/w) were examined using non-sieved excipients and the dry powder hybrid mixing device enabled the development of successful blends within compendial requirements and low relative standard deviation.

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Oral solid self-nanoemulsifying drug delivery systems of candesartan citexetil

Abstract

Candesartan cilexetil is an ester prodrug antagonist to angiotensin II receptor type 1 (AT1) used in management of many cardiovascular diseases. The absolute bioavailability of candesartan cilexetil is about (14–40%). Therefore, the paper aim was to prepare and evaluate solid self-nanoemulsifying drug delivery systems for candesartan cilexetil in order to improve its solubility, dissolution and stability. Solubility study was run in different vehicles to select the best excipients for dissolving candesartan cilexetil. Pseudo-ternary phase diagrams were constructed at 1:1, 2:1, 3:1 and 4:1 ratios and four formulations were prepared using various concentrations of cinnamon oil, tween 80 with poloxamer 407 mixture and transcutol HP as oil, surfactant mixture and co-surfactant, respectively. After this step about (0.2 milliliter) of each formulation was adsorbed on to two different adsorbent mixtures set which were: avicel 101 with aerosil 200 and avicel 101 with dibasic calcium phosphate anhydrous resulted in eight solid nanoformulations. All prepared formulations were evaluated for particle size distribution, polydispersity index, zeta potential, scanning probe microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffractometry and in vitro drug dissolution. It was found that release rate and extent for all prepared formulations were significantly higher (p < 0.05) than marketed tablet as well as plain drug powder. It could be concluded from the study that self-nanoemulsifying drug delivery system is a promising approach to improve solubility, wettability, dissolution and stability of candesartan cilexetil.

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APIs & Excipients – A Global Regulatory Overview

Webinar

September 20, 2017 - 11:00am to 1:00pm

September 21, 2017 - 11:00am to 1:00pm

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3D printed oral solid dosage forms containing hydrochlorothiazide for controlled drug delivery

Abstract

3D printing has been recently employed in the design and fabrication of medicine, aiming to improve their properties and release behavior. In the current work an oral solid dosage form was designed by Fused Deposition Modeling (FDM), using a custom built filament comprised of a water soluble polymer polyvinyl alcohol (PVA), mannitol and hydrochlorothiazide (HCTZ) as model drug and further co-formulated via Hot-Melt Extrusion (HME). This composition was printed as the inner part of a three-compartment hollow cylinder dosage form using a dual extrusion 3D FDM printer, whereas the outer parts of the formulation consisted of water-insoluble polylactic acid (PLA). The produced formulations were characterized by means of differential scanning calorimetry (DSC), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). Release studies were performed in pH 1.2 and 6.8 whereas four-dimensional X-ray micro focus Computed Tomography (4D-CT), was employed to visualize volumetric and morphological changes of the formulations during the dissolution procedure. The results showed that HCTZ was incorporated in the amorphous state. Dissolution studies demonstrated that HCTZ exhibited zero-order kinetics whereas 4D-CT revealed a bi-directional smooth and homogenous reduction of PVA further corroborating the dissolution studies. The results showed that FDM printing might be used to ‘fine tune’ the release of drug molecules.

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Nanoemulsions as edible coatings

Edible coatings are used to preserve food quality but may serve to immobilize active ingredients on the food surface. Nanoemulsions are effective systems for encapsulating lipophilic active ingredients since the reduction of droplet size increases their solubility, stability and may enhance their biological activity. Therefore, this review aims to highlight the most important aspects in designing food nanoemulsions for active substances delivery and the recent advances in their application as edible coatings. Up to date, research studies confirm that nanoemulsion-based edible coatings can enhance the transport of antimicrobial substances to solid foods extending their shelf life. However, future studies should be oriented to assess the impact of nanoemulsions on the organoleptic properties of coated foods and their potential toxicity.

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Analysis of the origins of content non-uniformity in high-shear wet granulation

Abstract

In this study, the origins of granule content non-uniformity in the high-shear wet granulation of a model two-component pharmaceutical blend were investigated. Using acetaminophen as the active pharmaceutical ingredient (API) and microcrystalline cellulose as the excipient, the distribution of the API across the granule size classes was measured for a range of conditions that differed in the duration of the initial dry mixing stage, the overall composition of the blend and the wet massing time. The coarse granule fractions were found to be systematically sub-potent, while the fines were enriched in the API. The extent of content non-uniformity was found to be dependent on two factors – powder segregation during dry mixing and redistribution of the API between the granule size fractions during the wet massing phase. The latter was demonstrated in an experiment where the excipient was pre-granulated, the API was added later and wet massed. The content non-uniformity in this case was comparable to that obtained when both components were present in the granulator from the beginning. With increasing wet massing time, the extent of content non-uniformity decreased, indicating that longer wet massing times might be a solution for systems with a natural tendency for component segregation.

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Nanocrystals & loaded porous silica for increased oral bioavailability

Oral dosage form is considered as the most convenient and commonly employed route of drug delivery due to the ease of administration, high patient compliance, cost-effectiveness, least constraints and flexibility in the design (Krishnaiah 2010). Drug companies have invested extensive effort on the development of oral drug products. However, although several factors can affect the bioavailability of an orally administrated dosage, e.g. first-pass metabolism, pre-systemic metabolism and susceptibility to efflux mechanisms, poor aqueous solubility and low permeability have been proven as the most frequent causes of low bioavailability (Sakaeda, Okamura et al. 2001; Vieth, Siegel et al. 2004).

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Development of semisolid self-microemulsifying drug delivery systems (SMEDDSs) filled in hard capsules for oral delivery of aciclovir

Abstract

The study aimed to develop semisolid self-microemulsifying drug delivery systems (SMEDDSs) as carriers for oral delivery of aciclovir in hard hydroxypropylmethyl cellulose (HPMC) capsules. Six self-dispersing systems (SD1-SD6) were prepared by loading aciclovir into the semisolid formulations consisting of medium chain length triglycerides (lipid), macrogolglycerol hydroxystearate (surfactant), polyglyceryl-3-dioleate (cosurfactant), glycerol (hydrophilic cosolvent), and macrogol 8000 (viscosity modifier). Their characterization was performed in order to identify the semisolid system with rheological behaviour suitable for filling in hard HPMC capsules and fast dispersibility in acidic and alkaline aqueous media with formation of oil-in-water microemulsions. The optimal SMEDDS was loaded with aciclovir at two levels (2% and 33.33%) and morphology and aqueous dispersibility of the obtained systems were examined by applying light microscopy and photon correlation spectroscopy (PCS), respectively. The assessment of diffusivity of aciclovir from the SMEDDSs by using an enhancer cell model, showed that it was increased at a higher drug loading. Differential scanning calorimetry (DSC) analysis indicated that the SMEDDSs were semisolids at temperatures up to 50 °C and physically stable and compatible with HPMC capsules for 3 months storage at 25 °C and 4 °C. The results of in vitro release study revealed that the designed solid dosage form based on the semisolid SMEDDS loaded with the therapeutic dose of 200 mg, may control partitioning of the solubilized drug from in situ formed oil-in-water microemulsion carrier into the sorrounding aqueous media, and hence decrease the risk for precipitation of the drug.

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Pellets and Micropellets for oral multiparticulate dosage forms

TTC Workshop  10 - 12 October 2017 in Binzen/Germany

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Central composite design in HPMC granulation and correlations between product properties and process parameters

Abstract

Particulate solids have received great interest in many industrial fields for both marketing reasons and technological aspects. In this study granular systems were achieved by using a wet granulation process using hydroxypropyl methylcellulose (HPMC) and distilled water as the binder phase. Particulates with a defined size (450–2000 μm) and good flowability together with a high granulation process yield, to reduce manufacturing scrap, were produced. To this aim a bench scale low-shear rate granulator apparatus was used; three process parameters were varied (impeller rotation speed, binder volume at constant mass, and binder flow rate) and, for each parameter, three intensities have been used. HPMC granule production was planned using the Central Composite Design (CCD) statistical protocol, which allowed us to minimize the number of runs to be performed for obtaining information about the relationship between granule properties and process parameters. The produced granules were stabilized by using a dedicated dynamic drying apparatus, then separated by sieving and then characterized in terms of size and flowability properties. The results of the experimental campaign have been used to develop semi-empirical correlations between granulated product properties and process parameters. A second-order polynomial law has shown the best comparison between experimental data and model predicted values. These correlations can constitute a reliable tool to help us to know more on the effect of operative parameter changes in HMPC or similar particulate solid production.

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Tablet Coating

TTC Workshop  19 – 21 September 2017 in Binzen/Germany

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Continuous Manufacturing in Pharma

16 hours hands-on seminar on continuous OSD pharma processing.

TTC Workshop  07 – 09 NOVEMBER 2017 in Binzen/Germany

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Development and Optimization by Quality by Design Strategies of Frovatriptan Orally Disintegrating Tablets for Migraine Management.

BACKGROUND: Frovatriptan is a potent anti-migraine agent with unfavorable slow onset of action, available on the market as film-coated tablets.

OBJECTIVE: Optimization, by Quality by Designs strategies, of an orally disintegrating tablet (ODT) formulation of frovatriptan aimed to make its oral administration easier and its dissolution faster than the commercial tablets, thus improving its effectiveness in migraine management.

METHOD:  A screening D-optimal design was applied to investigate the effects of different levels of kind and amount of ODT special excipient and disintegrant agents (identified as the critical variables) on disintegration time (DT) and % drug dissolved at 30 s (%Diss), selected as the responses to optimize. The best excipients combination, emerged by the screening step, was in-depth investigated by a Response Surface Methodology.

RESULTS:  A design space was defined where every combination of the selected variables fulfilled the required values for the responses with P ≥ 95%. In particular, the optimized formulation (Pharmaburst® 60% and Na alginate 15%), showed DT = 1.62±0.08 s and %Diss= 9.02±0.47%, with good agreement between measured and calculated values. Moreover, the developed ODT complied with the USP uniformity weight and drug content requirements, exhibited proper hardness and low friability, and provided 100 % dissolved drug within 5 min.

CONCLUSIONS:  A frovatriptan ODT formulation was successfully developed by Quality by Design. It represents an effective alternative to conventional tablets, allowing easier oral administration (also to paediatric and geriatric people) and very faster drug dissolution, enhancing patient compliance and facilitating an earlier treatment of migraine attacks.

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Development of a solid dosage platform for the oral delivery of bilayer vesicles

Abstract

Within this work, we develop vesicles incorporating sub-unit antigens as solid dosage forms suitable for the oral delivery of vaccines. Using a combination of trehalose, dextran and mannitol, freeze-dried oral disintegrating tablets were formed which upon rehydration release bilayer vesicles incorporating antigen. Initial studies focused on the optimisation of the freeze-dry cycle and subsequently excipient content was optimised by testing tablet hardness, disintegration time and moisture content. The use of 10% mannitol and 10% dextran produced durable tablets which offered strong resistance to mechanical damage yet appropriate disintegration times and dispersed to release niosomes-entrapping antigen. From these studies, we have formulated a bilayer vesicle vaccine delivery system as rapid disintegrating tablets and capsules.

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Surface properties and morphology of selected polymers and their blends designed to mucoadhesive dosage forms

Abstract

In the mucoadhesive drug delivery systems the controlling mechanism is initiated by the wetting and swelling of the polymer matrix. In view of the above, the aim of our study was to analyze the effect of model saliva and gastric fluids on the wetting properties and sorption of selected mucoadhesive (Carbopol 974P NF, HEC) and film-forming (Kollidon VA 64) polymers as well as their blends. We considered two types of examined materials: individual polymers and their blends in the form of powders as well as in the form of compressed discs (blanc tablets). The contact angle measurements for powders were performed according to the Washburn method, using the capillary rise technique, whereas the sessile drop method was applied to the compressed discs of mucoadhesive polymers. The surface energy was determined by the OWRK method. The influence of composition of the polymer blends and pH of model fluids on the wetting properties and sorption of the polymer formulations was evaluated. Moreover, significant differences in the morphology, surface roughness and surface properties of mucoadhesion polymers considered were discussed.

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An investigation into the effects of excipient particle size, blending techniques and processing parameters on the homogeneity and content uniformity of a blend

Abstract

Powder blend homogeneity is a critical attribute in formulation development of low dose and potent active pharmaceutical ingredients (API) yet a complex process with multiple contributing factors. Excipient characteristics play key role in efficient blending process and final product quality. In this work the effect of excipient type and properties, blending technique and processing time on content uniformity was investigated. Powder characteristics for three commonly used excipients (starch, pregelatinised starch and microcrystalline cellulose) were initially explored using laser diffraction particle size analyser, angle of repose for flowability, followed by thorough evaluations of surface topography employing scanning electron microscopy and interferometry. Blend homogeneity was evaluated based on content uniformity analysis of the model API, ergocalciferol, using a validated analytical technique. Flowability of powders were directly related to particle size and shape, while surface topography results revealed the relationship between surface roughness and ability of excipient with high surface roughness to lodge fine API particles within surface groves resulting in superior uniformity of content. Of the two blending techniques, geometric blending confirmed the ability to produce homogeneous blends at low dilution when processed for longer durations, whereas manual ordered blending failed to achieve compendial requirement for content uniformity despite mixing for 32 minutes. Employing the novel dry powder hybrid mixer device, developed at Aston University laboratory, results revealed the superiority of the device and enabled the production of homogenous blend irrespective of excipient type and particle size. Lower dilutions of the API (1% and 0.5% w/w) were examined using non-sieved excipients and the dry powder hybrid mixing device enabled the development of successful blends within compendial requirements and low relative standard deviation.

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Nanosizing techniques for improving bioavailability of drugs

Abstract

The poor solubility of significant number of Active Pharmaceutical Ingredients (APIs) has become a major challenge in the drug development process. Drugs with poor solubility are difficult to formulate by conventional methods and often show poor bioavailability. In the last decade, attention has been focused on developing nanocrystals for poorly water soluble drugs using nanosizing techniques. Nanosizing is a pharmaceutical process that changes the size of a drug to the sub-micron range in an attempt to increase its surface area and consequently its dissolution rate and bioavailability. The effectiveness of nanocrystal drugs is evidenced by the fact that six FDA approved nanocrystal drugs are already on the market. The bioavailabilities of these preparations have been significantly improved compared to their conventional dosage forms. There are two main approaches for preparation of drug nanocrystals; these are the top-down and bottom-up techniques. Top-down techniques have been successfully used in both lab scale and commercial scale manufacture. Bottom-up approaches have not yet been used at a commercial level, however, these techniques have been found to produce narrow sized distribution nanocrystals using simple methods. Bottom-up techniques have been also used in combination with top-down processes to produce drug nanoparticles. The main aim of this review article is to discuss the various methods for nanosizing drugs to improve their bioavailabilities.

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Mechanical microencapsulation: The best technique in taste masking for the manufacturing scale - Effect of polymer encapsulation on drug targeting

Abstract

Drug taste masking is a crucial process for the preparation of pediatric and geriatric formulations as well as fast dissolving tablets. Taste masking techniques aim to prevent drug release in saliva and at the same time to obtain the desired release profile in gastrointestinal tract. Several taste masking methods are reported, however this review has focused on a group of promising methods; complexation, encapsulation, and hot melting. The effects of each method on the physicochemical properties of the drug are described in details. Furthermore, a scoring system was established to evaluate each process using recent published data of selected factors. These include, input, process, and output factors that are related to each taste masking method. Input factors include the attributes of the materials used for taste masking. Process factors include equipment type and process parameters. Finally, output factors, include taste masking quality and yield. As a result, Mechanical micro encapsulation obtained the highest score (5/8) along with complexation with cyclodextrin suggesting that these methods are the most preferable for drug taste masking.

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Solid state properties and drug release behavior of co-amorphous indomethacin-arginine tablets coated with Kollicoat® Protect

Abstract

A promising approach to improve the solubility of poorly water-soluble drugs and to overcome the stability issues related to the plain amorphous form of the drugs, is the formulation of drugs as co-amorphous systems. Although polymer coatings have been proven very useful with regard to tablet stability and modifying drug release, there is little known on coating co-amorphous formulations. Hence, the aim of the present study was to investigate whether polymer coating of co-amorphous formulations is possible without inducing recrystallization. Tablets containing either a physical mixture of crystalline indomethacin and arginine or co-amorphous indomethacin-arginine were coated with a water soluble polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® Protect) and stored at 23 °C/0 % RH and 23 °C/75 % RH. The solid state properties of the coated tablets were analyzed by XRPD and FTIR and the drug release behavior was tested for up to 4 h in phosphate buffer pH 4.5. The results showed that the co-amorphous formulation did not recrystallize during the coating process or during storage at both storage conditions for up to three months, which confirmed the high physical stability of this co-amorphous system. Furthermore, the applied coating could partially inhibit recrystallization of indomethacin during drug release testing, as coated tablets reached a higher level of supersaturation compared to the respective uncoated formulations and showed a lower decrease of the dissolved indomethacin concentration upon precipitation. Thus, the applied coating enhanced the AUC of the dissolution curve of the co-amorphous tablets by about 30%. In conclusion, coatings might improve the bioavailability of co-amorphous formulations.

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Application of a Biodegradable Polyesteramide Derived from L-Alanine as Novel Excipient for Controlled Release Matrix Tablets

Abstract

This pre-formulation study assays the capacity of the polyesteramide PADAS, poly (L-alanine-dodecanediol-L-alanine-sebacic), as an insoluble tablet excipient matrix for prolonged drug release. The flow properties of PADAS were suitable for tableting, and the compressibility of tablets containing exclusively PADAS was evaluated by ESEM observation of the microstructure. The tablets were resistant to crushing and non-friable and they did not undergo disintegration (typical features of an inert matrix). Tablets containing 33.33% sodium diclofenac (DF), ketoprofen (K) or dexketoprofen trometamol (DK-T) as a model drug, in addition with 66.67% of polymer, were formulated, and the absence of interactions between the components was confirmed by differential scanning calorimetry. Dissolution tests showed that PADAS retained DF and K and prolonged drug release, following a Higuchi kinetic. The tablets containing DK-T did not retain the drug sufficiently for prolonged release to be established. Tablets containing DK-T and 66.67, 83.33 or 91.67% PADAS, compressed at 44.48 or 88.96 kN, were elaborated to determine the influence of the polymer amount and of the compression force on DK-T release. Both parameters significantly delayed drug release, except when the proportion of polymer was 91.67%.

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Evaluation of retrograded starch as excipient for controlled release matrix tablets

Abstract

High amylose starch (HAS) was retrograded by two different methods. The physicochemical properties of the retrograded materials were evaluated and structural changes were highlighted. Micromeritics properties were demonstrated as suitable for the compression process. Hydrophilic matrices were prepared by dry granulation of the retrograded starch. The in vitro release of diclofenac sodium (DS) in media with different pH values (1.2 and 7.4) was evaluated. The release profiles demonstrated the lowering of drug release rates in acid medium, mainly when pectin was associated to the matrix by physical mixture. In enteric medium, increased rates of drug release were observed, so that t80% occurred at approximately 60 min, while for the tablets obtained with HAS, this time was of approximately 120 min. The matrix obtained with pectin (during retrogradation and by physical mixture) enabled a more effective control over the drug release rates, so that t80% of DS was 150 min and 210 min, respectively.

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Recent Trends in the Development of Chitosan-Based Drug Delivery Systems

The AAPS PharmSciTech theme Recent Trends in the Development of Chitosan-Based Drug Delivery Systems includes a topical collection of 14 papers including both articles from EUCHIS/ICCC 2015 plus other freely contributed manuscripts that passed the rigorous peer-review process.

 

The first article in the theme describes the development of miconazole nitrate buccal films. The in vitro antifungal activity showed significant activity of the model drug loaded into those films.

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Read full articles in the AAPS PharmSciTech theme Recent Trends in the Development of Chitosan-Based Drug DeliverySystems, guest edited by Claudio Salomon, Francisco M. Goycoolea, and Bruno Moerschbacher. 

A review of in vivo and in vitro aspects of alcohol-induced dose dumping

Abstract

This review provides a comprehensive list of in vivo and in vitro studies that have investigated alcohol induced dose dumping (AIDD) in modified release dosage forms. Of the numerous classes of drugs commercially available as modified release products, opioids, centrally acting drugs, and drugs with a narrow therapeutic index present high risks from dose dumping, despite being formulated in a manner that releases drug in a tailored or delayed fashion. Awareness of AIDD has led to the withdrawal of a few marketed products by Regulatory Agencies, and black box warnings on others. Since then, significant effort has focused on proving the robustness of a formulation when co-ingested with alcohol. Patient risk is deemed to be low if the formulation and its performance is unimpaired by the presence of 0–40% alcohol under in vivo and in vitro conditions.

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Dissolution Testing of Herbal Medicines: Challenges and Regulatory Standards in Europe, the United States, Canada, and Asia

ABSTRACT

Herbal medicines are the oldest method for treating diseases and at the same  time still the most commonly used worldwide. Although people in developing countries depend on traditional herbal medicines, herbal products also play an important role in the healthcare systems of industrialized countries due to ongoing health trends for substituting natural products for potentially harmful chemicals. The regulatory standards of various authorities for herbal medicines are not harmonized in regional classification and quality requirements. It is particularly difficult to oversee authority requirements for dissolution testing of herbal medicines due to widely varying regulations. The aim of this article is to give a short overview of regulatory classification and dissolution standards of herbal medicinal products with regard to regional differences in Europe, the United States, and Asia. Furthermore, challenges in dissolution method development for herbal medicines are discussed. Because the ingredients of herbal medicinal products o en cover a mixture of multiple herbal constituents, dissolution method development is much more complex than for defined single constituents.

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Heat Assisted Twin Screw Dry Granulation

ABSTRACT

A new ‘assisted' dry granulation method has been devised for the twin-screw granulator. The method may be beneficial to drug preparation as it limits heat exposure to only one barrel zone, much shorter than melt granulation. Its mechanism was investigated using four placebo formulations, each containing a polymer binder with a glass transition temperature lower than 130°C. Variables of study included screw configuration, screw speed, barrel zone temperature and moisture content. Granulated samples were characterized for size and porosity while feed powders were examined for their thermal transitions, inter-particle friction, cohesion, and sintering rate. Results indicated that granule coalescence relied upon melting of polymer binder in the kneading blocks by a combination of heat conducted from barrel and generated from screw speed friction. Successful granulation was possible with minimal addition of water, though varying the moisture content showed the relevance of the polymer's glass transition temperature and sintering progress.

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Comprehensive mucoadhesive study of anionic polymers and their derivate

Aim

The purpose was to compare the mucoadhesive properties of well-known anionic polymers such as alginate (AL), carboxymethyl cellulose (CMC), polycarbophil (PC) and hyaluronic acid (HA) with regards to potential improvement in mucoadhesiveness based on chemical modification.

Methods

AL, CMC, PC and HA, respectively, were modified with sulfhydryl groups of cysteine (CYS) on their polymeric backbone via amide bond formation. Viability and safety was evaluated on mucosal surface. Histology imaging was taken via H&E staining. Intense mucoadhesive studies were performed on mucosal tissue determining residence time, adhesion and total work of adhesion as well as maximum detachment force of unmodified and modified polymers, respectively.

Results

Both polymers, unmodified anionic and modified ones, exhibit no toxicity at all. Histology imaging was in good agreement with the viability study on the mucosal surface. Unmodified anionic polymers reveal limited mucoadhesiveness whereas modified polymers showed up to 2.18-fold, 2.77-fold, 16.29-fold and 59.23-fold more pronounced total work of adhesion in case of CMCCYS, HACYS, PCCYS and ALCYS, respectively.

Conclusion

This comprehensive study provides deep understanding for the appropriate choice of mucoadhesive excipient for the development of mucosal drug delivery systems.

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Development and evaluation of an oral fast disintegrating anti-allergic film using hot-melt extrusion technology

Abstract

The main objective of this novel study was to develop chlorpheniramine maleate orally disintegrating films (ODF) using hot-melt extrusion technology and evaluate the characteristics of the formulation using in vitro and in vivo methods. Modified starch with glycerol was used as a polymer matrix for melt extrusion. Sweetening and saliva-simulating agents were incorporated to improve palatability and lower the disintegration time of film formulations. A standard screw configuration was applied, and the last zone of the barrel was opened to discharge water vapors, which helped to manufacture non-sticky, clear, and uniform films. The film formulations demonstrated rapid disintegration times (6–11 s) and more than 95% dissolution in 5 min. In addition, the films had characteristic mechanical properties that were helpful in handling and storage. An animal model was employed to determine the taste masking of melt-extruded films. The lead film formulation was subjected to a human panel for evaluation of extent of taste masking and disintegration.

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Manufacturing classification system

«The proposal coming from the Manufacturing classification system (MCS) working group represents a “guideline” for the formulator, that might be used as far as possible adapting it to the specific active ingredient to be formulated and inserting its description into the pharmaceutical development section of the dossier».

 

Piero Iamartino coordinates the new AFI’s Pharmaceutical Technology working group, together with professor Andrea Gazzaniga of the University of Milan. He summarizes for Pharma World the history and final goals of the MCS initiative, originally proposed in 2014 by a British university-industry mixed working group led by representatives of three big pharma, Bristol-Myers Squibb, GlaxoSmithKline and AstraZeneca. AFI’s Pharmaceutical Technology group accepted the invitation of the authors of the paper published in Pharmaceutical Development and Technology1 aimed to review the potential of the proposed approach and how it could benefit the pharmaceutical industry.

 

«The introduction of a manufacturing classification system could help explain the quality-by-design approach to the regulatory authorities, highlighting that the manufacturing process has been developed taking into account quality criteria and the critical quality attributes of the active ingredient. The MCS would have no direct impact from the regulatory point of view: it would rather enrich the knowledge of the formulator, to be briefly explained in the dossier», explains Iamartino.

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Gastroresistant gelatin films prepared by addition of cellulose acetate phthalate

Abstract

Gastroresistant capsules are obtained mostly by using modified-release fill in hard capsules, or by coating the gelatin shell with acid-resistant polymers. Modification of the material used at the stage when the capsule shell is produced would reduce the complexity and cost of introducing new products to the market. Gastroresistant gelatin films were obtained by using commercial cellulose acetate phthalate (aqueous dispersion Aquacoat® CPD). Only films casted from non-alkalized mixtures showed no visible disintegration at pH from 1.2 (simulated gastric fluid) to 4.5 (phosphate buffer). Elasticity of the dry films was comparable with the one determined for non-modified gelatin films, however tear resistance was 2-fold smaller, but still acceptable for practical application.

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Processing Thermally Labile Drugs by Hot-Melt Extrusion: The Lesson with Gliclazide

Abstract

The formation of molecularly dispersed amorphous solid dispersions by the hot-melt extrusion technique relies on the thermal and mechanical energy inputs, which can cause chemical degradation of drugs and polymeric carriers. Additionally, drug degradation may be exacerbated as drugs convert from a more stable crystalline form to a higher energy amorphous form. Therefore, it is imperative to study how drug degrades and evaluate methods to minimize drug degradation during the extrusion process. In this work, gliclazide was used as a model thermally labile drug for the degradation kinetics and process optimization studies. Preformulation studies were conducted using thermal analyses, and liquid chromatography–mass spectroscopy to identify drug degradation pathways and to determine initial extrusion conditions. Formulations containing 10% drug and 90% AFFINISOL™ HPMC HME 100LV were then extruded using a twin screw extruder, and the extrudates were characterized using X-ray powder diffraction, modulated dynamic scanning calorimetry, and potency testing to evaluate physicochemical properties. The energies of activation for both amorphous gliclazide, crystalline gliclazide, and gliclazide solution were calculated using the Arrhenius equation to further guide the extrusion optimization process. Preformulation studies identify two hydrolysis degradation pathways of gliclazide at elevated temperatures. The activation energy study indicates a significantly higher degradation rate for the amorphous gliclazide compared to the crystalline form. After optimization of the hot-melt extrusion process, including improved screw designs, machine setup, and processing conditions, gliclazide amorphous solid dispersion with ∼95% drug recovery was achieved. The ability to process thermally labile drugs and polymers using hot-melt extrusion will significantly expand the possible applications of this manufacturing process.

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Determination of the release mechanism of Theophylline from pellets coated with Surelease® − a water dispersion of Ethyl cellulose

Abstract

The aim of this study was to investigate the water transport over free standing films based on the aqueous ethyl cellulose (EC) coating Surelease® and the drug (Theophylline) release mechanism from coated pellets. It was found that the main drug release rate from pellets was controlled by a diffusion mechanism. However, the drug release rate was altered by addition of sodium chloride to the external release medium. A decrease in the drug release rate when sodium chloride is added to the release medium has traditionally been used to indicate an osmotic drug release mechanism. However, our findings that the release rate decreased by sodium chloride addition could be explained by sodium chloride diffusing through the coating layer into the inner parts of the pellets, decreasing the solubility of Theophylline. This gave a reduced drug concentration gradient over the coating layer and thus a slower release rate. Furthermore, this study shows, as expected, that the transport of water through Surelease® films into the pellets was faster than the transport out of Theophylline (approx. seven times), which was the reason why the pellets were swelling during the release. It was also shown that the drug release rate, determined for both whole dose release and for single pellets, decreased with increasing thickness (from 16 to 51 μm) of the coating layer controlling the drug release rate.

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A novel hybrid solid dispersion film coat as a moisture barrier for pharmaceutical applications

Abstract

In the present study, a novel hybrid moisture barrier film coat, based on a solid dispersion of a stearic acid (SA) in hydroxypropyl cellulose (HPC) using a polymeric surface active agent (PSAA), has been developed. The hybrid free films, prepared by a solution casting method, were characterized by water vapor transmission rate, DSC, mechanical tests, SEM and contact angle measurement to assess the structure-properties relationships of the films. The hybrid film formulations were then used to coat tablets containing CaCl2 as a moisture absorbing agent to study the coating and sealing properties of the films. The results have shown that a specific weight ratio between the components, could considerably increase the barrier capability of the film against moisture as compared to either pure HPC or the combination of HPC and SA, while keeping the basic properties of the HPC. This specific feature, could be attributed to the presence of PSAA in the film, which may form micelle-like structures entrapping the SA, to result in a reduced interfacial tension and thus a tight integration between two opposing phases (HPC and SA). By this means the micro-sized SA particulates could be evenly dispersed within HPC matrix to obtain an efficient solid dispersion.

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Advanced Stability Predictions for Amorphous Pharmaceuticals

  • Basic fundamentals of amorphous pharmaceutical stability predictions
  • Overcoming the limitations of RTD temperature sensors
  • Molecular mobility – considering the different molecular motions that exist in amorphous pharmaceuticals
  • Predicting the long-term physical stability of materials based on these molecular motions

Sunny Bhardwaj

Sr. Scientist - Merck

@ DDF Summit August 28-29, 2017 in Boston 

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A Comparative Assessment of Nanocomposites vs. Amorphous Solid Dispersions Prepared via Nanoextrusion for Drug Dissolution Enhancement

Abstract

Nanoextrusion was used to produce extrudates of griseofulvin, a poorly water-soluble drug, with the objective of examining the impact of drug particle size and polymeric matrix type–size of the extrudates on drug dissolution enhancement. Hydroxypropyl cellulose (HPC) and Soluplus® were used to stabilize wet-milled drug suspensions and form matrices of the extrudates. The wet-milled suspensions along with additional polymer (HPC/Soluplus®) were fed to a co-rotating twin-screw extruder, which dried the suspensions and formed various extrudates. The extrudates were dry-milled and sieved into samples with two different sizes. A wet-milled suspension was also spray-dried in comparison to nanoextrusion. Due to differences in polymer–drug miscibility, two forms of the drug were prepared: extrudates with nano/micro-crystalline drug particles dispersed in the HPC matrix as a secondary phase (nano/microcomposites) and extrudates with amorphous drug molecularly dispersed within the Soluplus® matrix (amorphous solid dispersion, ASD). Under non-supersaturating conditions in the dissolution medium, drug nanocrystals in the HPC-based nanocomposites dissolved faster than the amorphous drug in Soluplus®-based ASD. While smaller extrudate particles led to faster drug release for the ASD, such matrix size effect was weaker for the nanocomposites. These findings suggest that nanocrystal-based formulations could outperform ASDs for fast dissolution of low-dose drugs.

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3D printed tablets loaded with polymeric nanocapsules: an innovative approach to produce customized drug delivery systems

Abstract

The generation of multi-functional drug delivery systems, namely solid dosage forms loaded with nano-sized carriers, remains little explored and is still a challenge for formulators. For the first time, the coupling of two important technologies, 3D printing and nanotechnology, to produce innovative solid dosage forms containing drug-loaded nanocapsules was evaluated here. Drug delivery devices were prepared by fused deposition modelling (FDM) from poly(ε-caprolactone) (PCL) and Eudragit® RL100 (EUD) filaments with or without a channelling agent (mannitol). They were soaked in deflazacort-loaded nanocapsules (particle size: 138 nm) to produce 3D printed tablets loaded with them, as observed by SEM. Drug loading was improved by the presence of the channelling agent and a linear correlation was obtained between the soaking time and the drug loading (r2 = 0.9739). Moreover, drug release profiles were dependent on the polymeric material of tablets and the presence of the channelling agent. In particular, tablets prepared with a partially hollow core (50% infill) had a higher drug loading (0.27% w/w) and faster drug release rate. This study represents an original approach to convert nanocapsules suspensions into solid dosage forms as well as an efficient 3D printing method to produce novel drug delivery systems, as personalised nanomedicines.

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Mesoporous Biomaterials: a Lexicon and Structured Bibliography of Reviews

Accessing mesoporous and nanostructure biomaterial information can be particularly time consuming and problematic due to the interdisciplinary nature of the field. Relevant papers can be found across a broad range of journals and various key words are needed to comprehensively retrieve information. A keyword lexicon and themed bibliography of over 250 review articles from more than 100 different journals has therefore been assembled to aid students and researchers in this expanding eld. Reviews dedicated to fabrication of mesoporous materials and some key characterisation techniques are grouped together. Reviews focussed on specific medical issues like biocompatibility and toxicological testing are also provided. Medical applications that have been the focus of reviews include drug delivery, cancer therapy, medical imaging, orthopaedics, tissue engineering, bio ltration, biosensing and bioanalysis. The following mesoporous materials also have had dedicated reviews on biomedical uses: silica, silicon, silicates, metallic biomaterials, metal organic frameworks, carbonaceous materials, calcium phosphates, titania, and alumina.

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Mesoporous magnesium carbonate as a drug delivery vehicle for stabilising amorphous drugs and regulating their release rate

In today’s drug discovery, the number of candidate drugs based on new molecular entities with poor aqueous solubility is increasing. Since poor aqueous solubility of an active pharmaceutical ingredients (APIs) is associated with low bioavailability and thus limite their therapeutic effect, this is often a great challenge in the development of new drugs when oral administration is the preferred route of administration. A number of different strategies have been developed to circumvent this problem where salt formulations of an API is the most widely employed method. However, new strategies are needed since there is no one solution that solves this issue for all substances. In recent time, the concept of stabilizing poorly soluble APIs in their amorphous form has gained a lot of attention since amorphous compounds exhibit a higher apparent solubility compared to their crystalline counterparts. Amorphous substances are prone to crystallize if left in a non-constricted environment and thus need to be stabilized if the amorphous state is to be conserved until administration. Inorganic mesoporous materials have been proposed as an interesting type of excipients that can conserve the amorphous state of APIs.

In this work, the focus was to investigate the possibilities of using a mesoporous type of magnesium carbonate to stabilize the amorphous state of different APIs. Due to the nanometer sized pores in the material, complete conservation of amorphous APIs was obtained. This resulted in both an increase in in vitro release rate and a higher solubility of the substances which may translate to both a faster onset of action and an improved therapeutic effect of the APIs in a clinical situation. The long term stability of formulations was also investigated showing promising results.

The results presented in this work show that mesoporous magnesium carbonate represents an interesting type of excipient for oral formulations of APIs with poor aqueous solubility.

Keywords: mesoporous, magnesium carbonate, drug delivery, solubility enhancement, bioavailability, pharmacokinetics, diffusion release, controlled release

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Nanoporous Silica Particles for Enhanced Drug Performance: Applications Beyond Increasing Solubility

  • Nanologica’s nanoporous silica technology is a versatile drug delivery platform that addresses formulation challenges for improved clinical benefit
  • Key applications of NLAB SilicaTM are enhancing bioavailability, overcoming pH-dependent solubility issues and improving PK variability
  • Two case studies of reformulating anti-infectives with NLAB SilicaTM will illustrate how a Drug Delivery technology can be used for repurposing of marketed drugs
  • How value can be maximised by the right collaboration models between technology partner and pharma Company

Nanologica @ DDF Summit Boston

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Molecular Dynamics Simulations of Amorphous Systems

  • MD simulations reveal molecular interactions that may facilitate interpretation of experimental data
  • Energy calculations enable estimates of amorphous miscibility
  • Water uptake and the influence of water on drug-excipient interactions can be explored
  • Water clustering leads to domains having enhanced mobility

Bradley D. Anderson

Professor, Department of Pharmaceutical Sciences

University of Kentucky @ DDF Summit August 28-29, 2017 in Boston

 

Lubrizol Invests $60 Million to Expand Particle Sciences, Vesta and Other Facilities in 2017

CLEVELAND, June 6, 2017 /PRNewswire/ -- The Lubrizol Corporation announces its LifeSciences business continues to invest in its key capabilities through a variety of planned expansions.  During this latest phase, a $60 million investment will focus on new product solutions, capacity expansion and additional cGMP manufacturing. These investments will strengthen the excipients, polymers, drug formulation and manufacturing, and medical device contract manufacturing capabilities at Lubrizol LifeSciences' global facilities.

 

Commercial drug product manufacturing will be added at the company's Particle Sciences facility in Bethlehem, PA. Leveraging the company's knowledge in complex formulations and production, the facility will be adjacent to the existing development and clinical trial manufacturing site, offering customers a seamless flow from development through manufacturing. This new space, which is expected to be operational in the fourth quarter of 2017, will accommodate both sterile and non-sterile products, highly potent compounds, and organic solvent processing.    

 

Additionally, LifeSciences is investing to expand its global facilities for excipients, polymers and contract manufacturing, with a focus on quality and efficiency. This capital investment will impact multiple sites to increase in-house engineering capacity across the LifeSciences portfolio of medical and pharmaceutical applications. This includes new investments in design, manufacturing and sterilization technologies for the production of interventional catheters and long-term implantable devices, an area of strategic importance to the medical device segment.

 

"We have significantly enhanced our capabilities through the combination of strong polymer technology, application know-how and world-class manufacturing," states Deb Langer, vice president, Lubrizol Personal Home and Health Care. "As healthcare companies look for total solution providers, we continue to invest in the right areas to provide valuable offerings where our customers are experiencing the most growth."

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NEWS PROVIDED BY

The Lubrizol Corporation 

06 Jun, 2017, 11:00 ET

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Novel nano-cellulose excipient for generating non-Newtonian droplets for targeted nasal drug delivery

PURPOSE: Thickening polymers have been used as excipients in nasal formulations to avoid nasal run-off (nasal drip) post administration. However, increasing the viscosity of the formulation can have a negative impact on the quality of the aerosols generated. Therefore, the study aims to investigate the use of a novel smart nano-cellulose excipient to generate suitable droplets for nasal drug delivery that simultaneously has only marginally increased viscosity while still reducing nasal drips.

METHODS: Nasal sprays containing the nano-cellulose at different concentrations were investigated for the additive's potential as an excipient. The formulations were characterised for their rheological and aerosol properties. This was then compared to the conventional nasal spray formulation containing the single-component hydroxyl-propyl cellulose (HPMC) viscosity enhancing excipient.

RESULTS: The HPMC-containing nasal formulations behave in a Newtonian manner while the nano-cellulose formulations have a yield stress and shear-thinning properties. At higher excipient concentrations and shear rates, the nano-cellulose solutions have significantly lower viscosities compared to the HPMC solution, resulting in improved droplet formation when actuated through conventional nasal spray.

CONCLUSIONS: Nano-cellulose materials could potentially be used as a suitable excipient for nasal drug delivery, producing consistent aerosol droplet size and enhanced residence time within the nasal cavity with reduced run-offs compared to conventional polymer thickeners.

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Improving Patient Convenience: Challenges from the Formulation Front

  • Patient centered integrated device implementation in early development
  • Role of developability and pre-formulation development
  • Analytical tools and workflows to assess device ability potential of therapeutic proteins.

Bernardo Perez-Ramírez, MSc, Ph.D.

Senior Scientific Director, Global Pharmaceutical Development-Biologics 

Sanofi

Plenary @ DDF Summit August 28-29, 2017 in Boston 

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Efficacy and Safety of a Chewable Methylphenidate Extended-Release Tablet in Children with Attention-Deficit/Hyperactivity Disorder

Objective: This phase 3, laboratory classroom study assessed the efficacy and safety of methylphenidate hydrochloride extended-release chewable tablets (MPH ERCT) compared with placebo in children with attention-deficit/hyperactivity disorder (ADHD).

Methods: Following a 6-week, open-label, dose-optimization period, children 6–12 years of age (n = 90) with ADHD were randomly assigned to double-blind MPH ERCT at the final optimized dose (20–60 mg/day) or placebo. After 1 week of double-blind treatment, efficacy was assessed predose and 0.75, 2, 4, 8, 10, 12, and 13 hours postdose in a laboratory classroom setting. The primary efficacy measure was the average of postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores, analyzed using a mixed-model, repeated-measures analysis. Secondary efficacy measures included Permanent Product Measure of Performance (PERMP) total number of problems attempted and total number of problems correct. Safety assessments included adverse event (AE) monitoring and the Columbia-Suicide Severity Rating Scale (C-SSRS).

Results: MPH ERCT treatment statistically significantly reduced the average of all postdose SKAMP-Combined scores versus placebo (least-squares mean difference [95% confidence interval], −7.0 [−10.9, −3.1]; p < 0.001). Statistically significant treatment differences in SKAMP-Combined scores were observed at 2 hours postdose through 8 hours postdose (p-values <0.001). Statistically significant differences between MPH ERCT and placebo in PERMP total number of problems attempted and total number of problems correct were observed at 0.75 hours postdose through 8 hours postdose (p-values ≤0.049). Common AEs in the open-label period (≥5%) were decreased appetite, upper abdominal pain, mood swings, irritability, insomnia, upper respiratory tract infection (URTI), dysgeusia, and headache; URTI was the only AE reported by >1 subject receiving MPH ERCT in the double-blind period (placebo: URTI, contusion, wound, and initial insomnia). No suicidal ideation or behavior was reported on the C-SSRS at baseline or at any postbaseline assessment.

Conclusions: MPH ERCT 20–60 mg significantly improved ADHD symptoms compared with placebo at 2 hours postdose through at least 8 hours postdose. MPH ERCT was generally safe and well tolerated, with a safety profile consistent with other MPH ER formulations. ClinicalTrials.gov Identifier: NCT01654250.

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Trends in Excipient Demand

Excipients play a key role in helping pharmaceutical manufacturers serve patients better through improved compliance and efficacy of treatment. They also help reduce developmental costs and provide opportunities to differentiate products through new modes of drug delivery.

Experts identify several trends driving excipient demand: solubility and bioavailability challenges, as well as the desire to increase the lifecycle of a drug, improve manufacturing efficiency and address the growing bioequivalence market.

PM1706 Insights Chart1Development of new treatments for chronic diseases, increased access to medication through generic drug production, increased research and development spending, growing competition, and new technologies are driving these trends, says Bosh Chattopadhyay, business director, BASF Pharma Solutions.

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In vitro and in vivo behavior of ground tadalafil hot-melt extrudates: How the carrier material can effectively assure rapid or controlled drug release

Abstract

Different types of ground hot-melt extrudates loaded with 10, 20 or 30 % of the poorly water-soluble drug tadalafil were prepared and characterized in vitro and in vivo (in rats). Soluplus was used as an amorphous carrier material, whereas mannitol and lactitol were studied as crystalline matrix formers. The systems were characterized using X-ray powder diffraction, thermogravimetric analysis coupled with quadruple mass spectrometry, differential scanning calorimetry, X-ray computed microtomography, in vitro drug release measurements and monitoring of drug plasma levels upon oral administration to rats. The pure drug substance and physical mixtures of tadalafil with the carrier materials were used as references. Importantly, the bioavailability of this poorly water-soluble drug could be substantially increased with the proposed formulations, and the in vitro and in vivo release rates could be effectively adjusted by choosing the appropriate type of carrier material: Whereas mannitol-based ground hot-melt extrudates rapidly released the drug and led to an early rise in drug plasma concentrations, Soluplus-based systems released tadalafil more slowly, resulting in delayed plasma peaks. These behaviors could be explained by the rapid disintegration/dissolution of the porous mannitol-based formulations, whereas Soluplus significantly swelled and the dissolved drug had to diffuse through the polymeric network prior to release. Blending these formulations can be expected to allow providing elevated drug concentrations in vivo during prolonged periods of time upon one single administration with a rapid onset of drug action.

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Application of ultrasound-assisted compression in pharmaceutical technology. Design and optimization of oral sustained-release dosage forms

Abstract

Ultrasound-assisted compression (USAC) is a technology combining a conventional compression process and US irradiation. These mechanical and thermal effects lead to heating, melting and sintering of materials. This article reviews the principles of ultrasound-assisted compression and its main applications in pharmaceutical technology. Physical properties of the materials and process parameters such as time, energy and inter-punch distances should be carefully controlled to guarantee reproducibility and a complete transition of the material. The application of ultrasounds during compression improves the mechanical strength of tablets, a clear advantage for formulations with high-doses of poor compressible drugs. Ultrasounds have also demonstrated its usefulness as a technique to prepare solid dispersions, enhancing the bioavailability of poorly soluble drugs. The formulation of sustained-release oral dosage forms has also benefit from the application of USAC, as a better control of drug release with a minor quantity of excipient could be obtained. The continuum percolation model provides a physical basis to explain the important decrease in the excipient percolation threshold using this technology. This model together with the quantification of the Excipient Efficiency parameter, are valuable tools to understand the drug release properties from sustained-release systems.

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New Excipients to Meet the Demands of a Challenging Industry

Current trends in the pharma market, such as the discovery of increasingly lipophilic APIs, macromolecules, and biological actives have created a need for a more in-depth understanding of existing excipients, as well as the creation of new excipients, says Karen A. Coppens, Global Marketing Manager for Dow. “For example, there are few excipients that are designed for processes such as hot melt extrusion or spray drying to enable solubility enhancement of highly lipophilic insoluble APIs,” she says. As such, a number of new products have been introduced that are modifications of existing monographed excipients.

 

In addition, continuous manufacturing has put increased demand on the performance of existing excipients, says True L. Rogers, RPh, PhD, Technologies Leader at Dow. Similarly, for the delivery of biosimilars, there are few approved excipients that can be successfully utilized. 

 

“Overall there is a strong trend that suggests the current monographed ingredients will not continue to be sufficient to support the newly discovered actives in the near future and new excipients will be required,” says William Porter III, PhD, Dow Associate Research Scientist.

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SPRAY-DRIED DISPERSIONS - Particle Engineering of Spray Dried Dispersions: Considerations for Downstream Processing

Amorphous solid dispersions (ASD) are a common formulation approach for orally delivered small molecule active pharmaceutical ingredients (APIs) whose oral bioavailability (BA) is limited by dissolution rate and/or solubility in the gastrointestinal tract. Some of the foremost reasons this method has become so prevalent are the large potential for gains in bioavailability, easily assessable and mature manufacturing platforms, and straightforward integration of the resultant dispersions into an oral solid dosage form. Given the amorphous form of the API has significantly higher free energy than its neutral crystal form, it will have a higher aqueous solubility, and therefore, a more rapid dissolution rate. For these reasons, it is fairly straightforward to formulate an ASD that has improved BA compared to its crystalline form. However, it can be challenging to formulate a shelf-stable ASD that maximizes absorption potential and at the same time optimizes attributes amenable for downstream processing into an oral solid dosage form.

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Roquette signs agreement to acquire Itacel and reinforce its global

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Overview of Multiparticulate Systems for Oral Drug Delivery

Abstract

Oral route remains the gold standard for drug delivery despite the new trends in the development of complex biotech therapeutic agents under specialty or biologic categories. This is mainly due to the patient preference for solid dosage forms, convenience of administration, accuracy of dosing, and therefore safety of the patients. In addition, the technologies involved in development and manufacture of tablets and capsules are well established and understood by scientists and regulators. Moreover there is a huge capacity, and capability already exists in most corners of the world, which means no new significant investments are required in order to develop and manufacture tablets and capsules. The development time of solid dosage forms is generally short, and manufacturing is fast, with high yields. The finished solid dose products exhibit very good stability when formulated and packaged appropriately. Therefore, the most common dosage types for oral drug delivery are tablets and capsules, and they will remain popular by the producers and users. According to the IMS Health data [1], total pharmaceutical market in 2015 was more than $950 billion (USD) with a compound annual growth of around 5% over the last 3–5 years. Over $475 billion were oral solid dosage forms consisting a staggering 1675 billion counting units of solid dosages in 2015. Multiparticulate sales were in the order of $34 billion and around 91 billion counting units and a growth of around 6% in 2015. There are many drug products in the market place that use multiparticulate drug delivery technology and an increasing number of pipeline products which are under development.

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EXCIPIENT UPDATE - Solvent-Less Film Coatings: New Ethylcellulose Grade Enables Rapid Dry Powder Coating

INTRODUCTION

Ethylcellulose is a widely used film-forming polymer used to impart modified-release characteristics or mask poor-tasting ingredients. Ethylcellulose is broadly accepted due to its outstanding safety profile and ease of use in conventional spray-coating equipment. Film-coating operations with ethylcellulose can be completed using solutions of ethylcellulose in organic solvents or from aqueous dispersions. ETHOCELTM brand ethylcellulose is the oldest trademarked brand available from The Dow Chemical Company and continues to be an exciting source of innovation. Dow’s constant pursuit of production excellence has resulted in an ethylcellulose product that adheres to exceptionally narrow viscosity limits, contains fewer insoluble fibers, and is reproducibly ethoxylated. With the introduction of the new ETHOCEL High Productivity (HP) grade, these advanced features have been further optimized for use in dry powder layering processes using rotor granulation technology.

 

DRAWBACKS OF TRADITIONAL SYSTEMS

Traditional spray-coating systems of ethylcellulose rely on dissolution of the polymer into a solvent to apply the coating onto the substrate. The film-formation process occurs by atomizing the solution into small droplets that coalesce on the surface of the substrate, allowing the carrier medium to evaporate, leaving an ethylcellulose film on the substrate. This process is repeated hundreds of times during the coating process, resulting in many layers of ethylcellulose that create a solid, homogenous film. This process is well understood and allows for great film formation, providing stable, reproducible coatings.

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Ashland Speciality Ingredients Belgium site receives EXCiPACT GMP certification

EXCiPACT asbl is delighted to announce that the Ashland Speciality Ingredients site in Doel, Belgium has recently been awarded an EXCiPACT GMP Certificate from SGS, one of EXCIPACT’s internationally-recognised Certification Bodies.

The Certificate demonstrates that the Ashland Speciality Ingredients (ASI) site in Doel, Belgium, manufactures pharmaceutical excipients according to the EXCiPACT Good Manufacturing Practice (GMP) Certification Standard. Its scope covers the production of methylcellulose (MC), hydroxypropylmethylcellulose (HPMC) and methylhydroxyethylcellulose (MHEC) as pharmaceutical excipients.

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3D Printed Orodispersible Films With Aripiprazole

Abstract

Three dimensional printing technology is gaining in importance because of its increasing availability and wide applications. One of the three dimensional printing techniques is Fused Deposition Modelling (FDM) which works on the basis of hot melt extrusion–well known in the pharmaceutical technology. Combination of fused deposition modelling with preparation of the orodispersible film with poorly water soluble substance such as aripiprazole seems to be extra advantageous in terms of dissolution rate. 3D printed as well as casted films were compared in terms of physicochemical and mechanical properties. Moreover, drug-free films were prepared to evaluate the impact of the extrusion process and aripiprazole presence on the film properties. X-ray diffractometry and thermal analyses confirmed transition of aripiprazole into amorphous state during film preparation using 3D printing technique. Amorphization of the aripiprazole and porous structure of printed film led to increased dissolution rate in comparison to casted films, which, however have slightly better mechanical properties due to their continuous structure. It can be concluded that fused deposition modelling is suitable technique and polyvinyl alcohol is applicable polymer for orodispersible films preparation.

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An explorative analysis of process and formulation variables affecting comilling in a vibrational mill: The case of Praziquantel

Abstract

Praziquantel, a BCS II class anthelmintic drug used for the treatment of schistosome infections, was coground in a vibrational mill with different polymers (linear and crosslinked povidone, copovidone and sodium starch glycolate). An explorative analysis of formulation variables (drug-polymer wt ratio and polymer type) and process parameters (type of grinding media, grinding time and frequency) was carried out with the help of an experimental screening design. The influence of the above mentioned factors on three PZQ characteristics (residual crystallinity, water solubility enhancement and drug recovery) was studied. The variation of carrier amount proved to be by far the most important variable affecting all the experimental responses. A lower impact and, in some cases, rather null effect, had the variation of the process variables. All coground systems were characterized by a high amorphous degree and a solubility significantly higher than the API. A very promising product was obtained by processing at 20 Hz for 4 h, using 3 spheres of 15 mm as grinding media, i.e. a coground having a 50% API content, showing a 4.6-fold greater solubility at 20 °C than pure praziquantel. This product maintained the same antischistosomal activity of pure API and was both physically and chemically stable for at least 6 months.

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Natural lipids-based NLC containing lidocaine: From pre-formulation to in vivo studies

Abstract

In a nanotechnological approach we have investigated the use of natural lipids in the preparation of nanostructured lipid carriers (NLC). Three different NLC composed of copaiba oil and beeswax, sweet almond oil and shea butter, and sesame oil and cocoa butter as structural matrices were optimized using factorial analysis; Pluronic® 68 and lidocaine (LDC) were used as the colloidal stabilizer and model encapsulated drug, respectively. The optimal formulations were characterized by different techniques (IR-ATR, DSC, and TEM), and their safety and efficacy were also tested. These nanocarriers were able to upload high amounts of the anesthetic with a sustained in vitro release profile for 24 h. The physicochemical stability in terms of size (nm), PDI, zeta potential (mV), pH, nanoparticle concentration (particles/mL), and visual inspection was followed during 12 months of storage at 25 °C. The formulations exhibited excellent structural properties and stability. They proved to be nontoxic in vitro (cell viability tests with Balb/c 3T3 fibroblasts) and significantly improved the in vivo effects of LDC, over the heart rate of zebra fish larvae and in the blockage of sciatic nerve in mice. The results from this study support that the proper combination of natural excipients is promising in DDS, taking advantage of the biocompatibility, low cost, and diversity of lipids.

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Can natural polymers assist in delivering insulin orally?

Abstract

Diabetes mellitus is one of the most grave and lethal non communicable diseases. Insulin is normally used to medicate diabetes. Due to bioavailability issues, the most regular route of administration is through injection, which may pose compliance problems to treatment. The oral administration thus appears as a suitable alternative, but with several important problems. Low stability of insulin in the gastrointestinal tract and low intestinal permeation are some of the issues. Encapsulation of insulin into polymer-based particles emerges as a plausible strategy. Different encapsulation approaches and polymers have been used in this regard. Polymers with different characteristics from natural or synthetic origin have been assessed to attain this goal, with natural polymers being preferable. Natural polymers studied so far include chitosan, alginate, carrageenan, starch, pectin, casein, tragacanth, dextran, carrageenan, gelatine and cyclodextrin. While some promising knowledge and results have been gained, a polymeric-based particle system to deliver insulin orally has not been introduced onto the market yet. In this review, effectiveness of different natural polymer materials developed so far along with fabrication techniques are evaluated.

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Investigation of polymorphic transitions of piracetam induced during wet granulation

Abstract

Piracetam was investigated as a model API which is known to exhibit a number of different polymorphic forms. It is freely soluble in water so the possibility exists for polymorphic transformations to occur during wet granulation. Analysis of the polymorphic form present during lab-scale wet granulation, using water as a granulation liquid, was studied with powder X-ray diffraction and Raman spectroscopy as off-line and inline analysis tools respectively. Different excipients with a range of hydrophilicities, aqueous solubilities and molecular weights were investigated to examine their influence on these solution-mediated polymorphic transitions and experimental results were rationalised using molecular modelling. Our results indicated that as an increasing amount of water was added to the as-received piracetam FIII, a greater amount of the API dissolved which recrystallised upon drying to the metastable FII(6.403) via a monohydrate intermediary. Molecular level analysis revealed that the observed preferential transformation of monohydrate to FII is linked with a greater structural similarity between the monohydrate and FII polymorph in comparison to FIII. The application of Raman spectroscopy as a process analytical technology (PAT) tool to monitor the granulation process for the production of the monohydrate intermediate as a precursor to the undesirable metastable form was demonstrated.

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Prediction of effects of punch shapes on tableting failure by using a multi-functional single-punch tablet press

Abstract

We previously determined “Tableting properties” by using a multi-functional single-punch tablet press (GTP-1). We proposed plotting “Compactability” on the x-axis against “Manufacturability” on the y-axis to allow visual evaluation of “Tableting properties”. Various types of tableting failure occur in commercial drug production and are influenced by the amount of lubricant used and the shape of the punch. We used the GTP-1 to measure “Tableting properties” with different amounts of lubricant and compared the results with those of tableting on a commercial rotary tableting machine. Tablets compressed with a small amount of lubricant showed bad “Manufacturability”, leading to sticking of powder on punches. We also tested various punch shapes. The GTP-1 correctly predicted the actual tableting results for all punch shapes. With punches that were more likely to cause tableting failure, our system predicted the effects of lubricant quantity in the tablet formulation and the occurrence of sticking in the rotary tableting machine.

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5 Advantages of Calibrating Your Equipment At An Accredited Lab

In the manufacturing industry, equipment precision and instrument accuracy play a large role in the overall turnover of the organization. This is because the performance of the machinery and its accuracy in terms of output can significantly alter the quality of the goods being produced. Operational accuracy is especially important in the pharma and bio-tech industries as their products are generally consumables and are subject to regular audits by regulatory bodies like the FDA; as well as quality checks by suppliers.

 

And in order to be able to maintain operational efficiency, such manufacturing concerns are required to regularly calibrate their equipment and machinery on a regular basis. While calibration can be done in-house, most organizations prefer to avail the services of third party calibration labs due to the number of benefits they offer. Following are the various features of an accredited calibration lab that prove to be advantageous to manufacturing concerns: 

  • Servicing Proficiency

Working with an accredited lab gives you a greater assurance of quality as the lab has been vetted for its accuracy by an independent accreditation body that assess whether industry standards and regulations are being met at the facility in concern. This guarantees the lab's competency with regard to the calibration services provided by them. 

  • Quality Control

Labs that provide accredited calibration services are required to undergo extensive research and training. This is done in order to develop and implement quality management systems that adhere to all state laws, rules and regulations to meet the standards set by the regulatory bodies such as the FDA. Since the calibration labs are required to go through such rigorous processes to validate their services, you are sure to receive a higher level of precision provided in a well-controlled environment. This is extremely beneficial to pharma and bio-tech companies as well as F&B manufacturing industries. 

  • Reduces Chances of Error

The accuracy of the lab’s calibration process itself is tested through strict assessment practices to ensure that product quality isn't affected due to inaccuracies or inefficient calibration. In case of pharma companies, this is a great area of concern as even a Minute inaccuracy can warrant a product recall or heavy fines due to Substandard manufacturing processes. This not only reduces the chances of error but also diminishes the possibility of incurring any additional losses due to improper

calibration. 

  • Cost Effective Auditing

The frequency of calibration auditing is relatively higher in companies that produce consumer goods such as the F&B industry and the pharmaceutical companies as they are required to conduct regular audits for suppliers. Therefore, it is better to choose a third party accreditation service over performing the calibration yourself as that will require additional validation from an accreditation body, thereby increasing the overall cost incurred by your organization towards equipment calibration.

  • Easy Tracking

By outsourcing your calibration processes to a third party calibration service provider, you are sure to

receive the highest level of precision in the calibration process, administered in a well controlled environment. This also ensures easy tracking of the calibration schedule of your equipments and all related details, making it easier to comply with the calibration audits.

 

As you can see, regular calibration of manufacturing equipment plays pivotal role in the smooth functioning of operations as well as the profitability of the manufacturing concern. Therefore, it is extremely important to ensure the calibration processes are also done with due diligence. So, remember to weigh your options carefully by understanding the pros and cons of availing such

services from third party providers while assessing their credibility to make the right decision.

 

Article written by Edward Simpson for

 

 

Author Bio

Edward Simpson is a seasoned Calibration and Technical Engineer working for RS Calibration Inc.

Edward has a knack for finding faults in machines and does not rest until they are rectified to perfection. He lives in Pleasanton, CA and can be contacted anytime for matters related to machines. He also invites people to visit his company www.rscal.com to learn more about the type of calibration work he does.

 

 

 

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Overview of solidification techniques for self-emulsifying drug delivery systems from industrial perspective

Abstract

Self-emulsifying drug delivery systems (SEDDS) are lipid formulations that improve solubility and oral bioavailability of the incorporated drug with poor biopharmaceutical properties. As liquids they are traditionally filled into soft or hard capsules. Transformation of SEDDS into solid dosage form has been extensively investigated in the recent years because solid dosage forms improve stability, handling and patient compliance. By using different solidification techniques selfemulsifying powders, granules, pellets and tablets can be produced. Appropriate excipients, solid carriers and processing parameters must be selected for each solidification technique to enable processability and preserve the self-emulsifying ability of the system upon its transformation into the solid formulation.In the present review various industrially applicable solidification techniques and excipients used for transforming liquid SEDDS into solid dosage forms with high production yield and good perspectives for being produced in large scales are discussed.

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Chitosan-clay nanocomposite microparticles for controlled drug delivery: Effects of the MAS content and TPP crosslinking

Abstract

Chitosan and clays can form nanocomposites via electrostatic interactions, offering an interesting potential as advanced drug delivery systems. Such nanocomposites can be prepared in the form of microparticles using spray-drying. The objective of this study was to produce and characterize spray-dried chitosan-magnesium aluminum silicate (MAS) nanocomposite microparticles, loaded with propranolol HCl. The effects of the MAS content and addition of the crosslinking agent sodium tripolyphosphate (TPP) were investigated. The incorporation of MAS rendered the microparticles less spherical. The spray-dried particles exhibited an intercalated nanocomposite structure, the drug being dispersed in an amorphous form and/or dissolved in the systems. Interestingly, propranolol release was sustained during several hours from all types of microparticles in 0.1 M HCl and phosphate buffer pH 7.4, and no burst release was observed. This is rather surprising, because the particles were in the lower micrometer range, and chitosan is soluble at acidic pH. These results highlight the importance of “drug–chitosan” and “drug–MAS” interactions in this type of nanocomposite microparticles. With increasing MAS content drug release clearly slowed down at low and neutral pH, whereas the incorporation of 1–3% TPP caused only a slight/moderate decrease in the release rate, irrespective of the type of release medium.

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Quality by Design approach for studying the impact of formulation and process variables on product quality of oral disintegrating films ☆

Abstract

The present investigation was carried out to understand the impact of formulation and process variables on the quality of oral disintegrating films (ODF) using Quality by Design (QbD) approach. Lamotrigine (LMT) was used as a model drug. Formulation variable was plasticizer to film former ratio and process variables were drying temperature, air flow rate in the drying chamber, drying time and wet coat thickness of the film. A Definitive ScreeningDesign: of Experiments (DoE) was used to identify and classify the critical formulation and process variables impacting critical quality attributes (CQA). A total of 14 laboratory-scale DoE formulations were prepared and evaluated for mechanical properties (%elongation at break, yield stress, Young’s modulus, folding endurance) and other CQA (dry thickness, disintegration time, dissolution rate, moisture content, moisture uptake, drug assay and drug content uniformity). The main factors affecting mechanical properties were plasticizer to film former ratio and drying temperature. Dissolution rate was found to be sensitive to air flow rate during drying and plasticizer to film former ratio. Data were analyzed for elucidating interactions between different variables, rank ordering the critical materials attributes (CMA) and critical process parameters (CPP), and for providing a predictive model for the process. Results suggested that plasticizer to film former ratio and process controls on drying are critical to manufacture LMT ODF with the desired CQA.

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Fasting during the ramadan: a challenge for patients with adrenal insufficiency

During the Ramadan, Muslims fast every day, from dawn to sunset, for a whole month. The fast is a stressful period when individuals abstain from eating and drinking and are therefore at risk of dehydration, fainting, low glucose levels, intense thirst, and asthenia. In patients with adrenal insufficiency who are deficient in one of the major metabolic and stress hormones in the body, cortisol, this may be fatal. Daily treatment with glucocorticoids usually hydrocortisone is essential. In the paper by Chihaoui et al. [1], patients with adrenal insufficiency were mostly on twice daily hydrocortisone regimes with the higher dose during fasting administered at the sunset meal and the lower dose at the predawn meal. During Ramadan taking medicine orally is considered breaking the fast....

 

The development of new formulations of hydrocortisone, with modified release mechanisms, could potentially reduce the risk for complications and adrenal crises during the Ramadan by extending 24-h cortisol exposure and delivering the right amount of cortisol in the appropriate time of the day. Chronocort®, administered twice daily with the higher dose at sunset and the lower dose at dawn has been shown to approximate the physiological cortisol circadian rhythm [12]. This formulation would allow those patients wanting to fast during the Ramadan respect their obligations and not break the fast...

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New Data Demonstrates Potential of Using In-Line Measured Coating Thickness to Predict Dissolution Profiles

 

New Data Demonstrates Potential of Using In-Line Measured Coating Thickness to Predict Dissolution Profiles

  • Is there a correlation between functional coating thickness and dissolution profiles?
  • Is Real-time dissolution prediction of a coating process using particle size data a viable control method? 
  • Will prediction data be reliable enough to use to use during process development, optimisation, scale up and transfer? 
  • Is there potential for process control or troubleshooting based on PSD trending?



New data is now available from a series of experiments conducted recently by industry leaders Glatt, Colorcon and Innopharma.  Colorcon Suglets® were coated with a Surelease® and Opadry®EC functional coating solution in a Glatt GPCG2® lab-scale fluid bed system.  In-Line particle size measurement was then performed using an Innopharma Eyecon2™particle analyser.

Chris O’Callaghan. Senior Product Manager, Innopharma Technology said “The Eyecon2™ data demonstrates clearly not only that a strong correlation exists between functional coating thickness,determined by particle size increase and dissolution profile but also that real-time dissolution prediction of a coating process using particle size data and a formulation-based model is a viable control method.


Christian Knopf, a Glatt PAT Expert, explains: “Hardware interface solutions for Eyecon2 and Glatt process equipment are available for lab, scale up and larger machines and the ethernet connectivity and the

Eyecon2’s OPC UA protocol allow complete integration into the GlattView Eco, Mega or Conti interface, making an additional Laptop unnecessary for operators who prefer to use the machine control system to control and access the data.”

To download the entire Application Note complete with experiment plan, materials and equipment used, results, conclusions please click here

Lab, Pilot and Commercial Scale Implementation

Innopharma Technology and Glatt have collaborated to develop Eyecon2 hardware interface and control system integration solutions for the most popular Glatt machines from the GPGC2 at lab scale to scale up and production machines. This facilitates rapid set up to generate real time in-line PSD data for deeper process understanding during QbD/DoE development and scale up activities and for process control during manufacture where required.


For more information please click here

Innopharma Technology is a division of Innopharma, specialised in the development of efficient, reliable and rapid direct measurement PAT analysers that support research, development and investigational experiments resulting in greater knowledge and more robust manufacturing processes.  
   
   

The Glatt Group has specialized in the manufacturing, handling and processing of powdery solids for the pharmaceutical, fine-chemical and food processing industries for more than 60 years. the core technology is the fluidized-bed method for granulation and drying, pelletization and coating of solids. The Glatt Group also offer laboratory, pilot and production equipment for the batch or continuous processes, product and process development and product handling for contract manufacturing. 

Colorcon® is a world leader in the development, supply and support of formulated products for the pharmaceutical industry.  Colorcon® provides a wide range of pharmaceutical film coatings and pharmaceutical formulation development assistance.  Fully formulated, complete film coating systems, modified release technologies, and excipients assist all pharmaceutical and nutritional supplement companies in the development of cost-effective, high quality products with superior performance and appearance.

 
This email was sent by oconnellc@innopharmalabs.com
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Revised IPEC GMP & GDP Guide for pharmaceutical Excipients available!

 

 

Announcing the publication and availability of the IPEC – PQG Good Manufacturing Practices (GMP) Guide for Pharmaceutical Excipients (Revised 2017) and IPEC Good Distribution Practices Guide for Pharmaceutical Excipients (Revised 2017).

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Propafenone HCl fast dissolving tablets containing subliming agent prepared by direct compression method

Abstract

Propafenone HCl (PPH), an antiarrhythmic drug, has a bitter taste, short half-life, delayed drug dissolution and side effects. Thus, the purpose of this work is to develop orally fast dissolving tablets (OFDTs) containing PPH to provide a rapid drug dissolution and subsequently give rapid onset of action of PPH as an antiarrhythmic drug. Moreover, OFDTs of PPH reduce its side effects and improve its bioavailability. Propafenone HCl (PPH), an antiarrhythmic drug, has a bitter taste, short half-life, delayed drug dissolution and side effects. Direct compression method was used for the preparation of 15 formulations OFDTs containing PPH using directly compressible excipients, subliming agent and superdisintegrants. The prepared tablets were undergone physical characterization, in vitro dissolution and stability studies. All pre- and post-compression tests met the pharmacopoeia specifications. In vitro dissolution of the prepared PPH OFDTs exhibited high dissolution rate than compared to the marketed tablets. It was found that the tablets prepared by using the higher concentration of crospovidone were found to dissolute the drug at a faster rate when compared to other concentrations. A formula containing croscarmellose sodium showed the higher present of PPH dissolved as compared to the other formulations. It was concluded that PPH OFDTs were formulated successfully with acceptable physical and chemical properties with rapid disintegration in the oral cavity, rapid onset of action, and enhanced patient compliance. It was found that F10 showed good stability upon storage at 25 and 40 °C for 3 months. Formulation of PPH OFDTs can result in a significant improvement in the PPH bioavailability since the first pass metabolism will be avoided.

Keywords Propafenone HCl; Orally fast disintegrating tablets (OFDTs); In vitro; Palatability; Stability

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The Need for Restructuring the Disordered Science of Amorphous Drug Formulations

Abstract

The alarming numbers of poorly soluble discovery compounds have centered the efforts towards finding strategies to improve the solubility. One of the attractive approaches to enhance solubility is via amorphization despite the stability issue associated with it. Although the number of amorphous-based research reports has increased tremendously after year 2000, little is known on the current research practice in designing amorphous formulation and how it has changed after the concept of solid dispersion was first introduced decades ago. In this review we try to answer the following questions: What model compounds and excipients have been used in amorphous-based research? How were these two components selected and prepared? What methods have been used to assess the performance of amorphous formulation? What methodology have evolved and/or been standardized since amorphous-based formulation was first introduced and to what extent have we embraced on new methods? Is the extent of research mirrored in the number of marketed amorphous drug products? We have summarized the history and evolution of amorphous formulation and discuss the current status of amorphous formulation-related research practice. We also explore the potential uses of old experimental methods and how they can be used in tandem with computational tools in designing amorphous formulation more efficiently than the traditional trial-and-error Approach.

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Quality Attributes and In Vitro Bioequivalence of Different Brands of Amoxicillin Trihydrate Tablets

Abstract:

Bacterial resistance and antibiotic drug effectiveness can be related to administering

generic products with a subtherapeutic dose or poor in vivo drug release. The aim of this study

was to investigate whether locally marketed amoxicillin tablets have the required chemical and

physical attributes, including in vitro bioequivalence performance. Five generic products (T1, T2,

T3, T4, and T5) containing combination of amoxicillin trihydrate and potassium clavulanate as 1 g

strength present in immediate release tablets were compared to the reference listed drug product

Augmentin® (R) for weight variation, friability, resistance to crushing, and chemical content of

amoxicillin. Difference (f 1) and similarity (f 2) factors were calculated to assess in vitro bioequivalence

requirements. The tablets from different products have shown compliance with the pharmacopeial

requirements of the performed tests. The measured resistance to crushing of tablets did not influence

the dissolution time. Three generic products released more than 85% of amoxicillin by the first 15 min

as did the reference product and were considered as bioequivalent products. T1 and T4 had f 1 values

of 16.5% and 25.4% respectively and their f 2 values were 44.5 and 34.6 respectively, indicating failure

to meet in vitro bioequivalence requirements. Tablet formulations can play an important role in

achieving bioequivalence. Independent investigations such as this study serve as an important tool

to reveal possible inferior or noncompliant products that may find their way to the market.

Keywords: amoxicillin tablets; bioequivalence; weight variation; friability; chemical content;

difference factor; similarity factor; HPLC Analysis

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Comparative Physicochemical Characterization of Chitosan from Shells of Two Bivalved Mollusks from Two Different Continents

Abstract

The need to turn seafood wastes that hitherto constitute an environmental pollution into important pharmaceutical excipients is gaining ground worldwide. This study investigated the extraction and characterization of chitosan from two oyster shells: Mytilus edulis and Laevicardium attenuatum from different continents. Demineralization and deproteinization were carried out to obtain chitin from the shells, followed by deacetylation to obtain chitosan. Percent yield, degree of deacetylation and other physicochemical characteristics were determined for the extracted chitosan from the two oyster shells. The yield of chitosan from Mytilus edulis was 51.8% and 43.8% from Laevicardium attenuatum. The degree of deacetylation (DD) of chitosan from Mytilus edulis was 69.6% while that of Laevicardium attenuatum was 37.3%. The Laevicardium attenuatumchitosan had higher swelling ratio. Calcium was the predominant metal ion in the two chitosan. While the micrograph of Mytilus edulis chitosan showed a non-uniform particle distribution, Laevicardium attenuatum chitosan showed a brick-like structure. This work has shown that it is more economical to produce chitosan from Mytilus edulis, and the polymer has higher degree of deacetylation. The higher degree of deacetylation implies better solubility and the chitosan could be more suitable as a permeation enhancer. The Laevicardium attenuatumchitosan could be more suitable for sustained release formulation.

Keywords: Chitosan, Mytilus edulis, Laevicardium attenuatum, Oyster Shells

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Characterization of new functionalized calcium carbonate-polycaprolactone composite material for application in geometry-constrained drug release formulation de

Keywords: Mineral-polymer composite, elastoplastic deformation, geometrically modified release, tablet formulation, TIC device, dry-coated tablet, functionalized calcium carbonate, polycaprolactone

Co-spray Drying with HPMC as a Platform to Improve Direct Compaction Properties of Various Tablet Fillers

Abstract

Many commonly used tablet fillers are not suitable for direct compaction process due to insufficient properties, mainly of flowability and compactability. This work therefore aimed to use co-spray drying with HPMC as a platform to improve direct compaction properties of various tablet fillers. Starch, calcium hydrogen phosphate dihydrate (DCPD), and mannitol were chosen as a representative of three types of commonly used fillers (i.e. organic macromolecules, water-insoluble inorganic salts, and water-soluble small molecular carbohydrates), respectively. The five-level central composite design-response surface methodology was used (i) to investigate the effects of HPMC level and solid content of the feed on various powder, tableting, and tablet properties of composite excipients, and (ii) to optimize the composition. The results showed that the impacts of the two factors on various properties of composite excipients showed great similarity, despite of significantly different primary properties of the parent fillers, and the HPMC level was the main contributor to the majority of the impacts. An increase in HPMC level significantly improved tablet tensile strength and various tableting parameters. For all the three fillers, their optimized composite excipients provided by the established models showed excellent performances as predicted. The platform suggested is confirmed to be effective and promising.

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Nanoporous Calcium Carbonate-Based Substrates for the Controlled Delivery of Functional Materials

The overall aim of this project was to study `functionalised' calcium carbonates (FCCs) for use as a carrier for the controlled release of `actives,' by permeation and diffusion, and is being proposed as an environmentally friendly and non-toxic pharmaceutical excipient, nutraceutical, and flavour carrier. The delivery of a drug to its target site in the appropriate amount and time-frame in order for it to have a controlled release effect whilst achieving the maximum therapeutic effect remains a topic of design and development for novel drug delivery systems.

 

FCCs encompass a family of new pharmaceutical excipients in which the conditions of manufacture follow strict process regulations with respect to the grade of reagents that are employed and the microbiological environment under which they are produced, and include freedom from organic polymers.

 

Adjustments to the FCC production process can be used to produce a wide range of different morphologies, and raise the possibility of tailoring the void structures of the particles to provide controlled release delivery vehicles for actives across many fields, including drugs and flavours. However, such tailoring can only be fully optimised by a fundamental characterisation of the way in which a drug, loaded into an FCC, then flows and diffuses out over a period of time to provide the delayed release.

 

It was found that adsorption on the FCC surface is selective, for example, saccharin does not become adsorbed from 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES) buffer solution, and neither does anethole from ethanol. FCC also does not adsorb the cationic probe benzyltrimethylammonium bromide (BTMAB) or the anionic probe sodium 2-naphthalenesulphonate (Na2NS). However, it was found that vanillin adsorbs onto the FCC in an amount of 2.00 ± 0.59 mg g^-1. Aspirin and vanillin adsorption from ethanolic solutions with various additions of water onto FCC TP was investigated and fitted with the Tóth isotherm. It was estimated that vanillin adsorbed onto around 17 %, and aspirin onto around 39 %, of the overall FCC TP surface area without the addition of any water. An equation was formulated in order to approximate the adsorption as a function of the FCC's surface coverage by the water. This is discussed in Chapter 4 and has also been published in a peer-reviewed academic journal (Levy et al., 2017)

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Sigachi Industries Pvt. Ltd. Indian site receives EXCiPACT GMP certification as pharmaceutical excipient suppliers

EXCiPACT asbl is delighted to announce that the Sigachi Industries Pvt. Ltd.’s site in Dahej, India has recently been awarded an EXCiPACT GMP Certificate from SGS, one of EXCIPACT’s internationally-recognised Certification Bodies.

The Certificate demonstrates that the Sigachi Industries Pvt. Ltd.’s site in Dahej, District Bharuch, Gujarat in India, manufactures pharmaceutical excipients according to the EXCiPACT Good Manufacturing Practice (GMP) Certification Standard. Its scope covers Manufacture and supply of cellulose based pharmaceutical excipients in the pharmaceutical industry.

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A Review of Disintegration Mechanisms and Measurement Techniques

Abstract

Pharmaceutical solid dosage forms (tablets or capsules) are the predominant form to administer active pharmaceutical ingredients (APIs) to the patient. Tablets are typically powder compacts consisting of several different excipients in addition to the API. Excipients are added to a formulation in order to achieve the desired fill weight of a dosage form, to improve the processability or to affect the drug release behaviour in the body. These complex porous systems undergo different mechanisms when they come in contact with physiological fluids. The performance of a drug is primarily influenced by the disintegration and dissolution behaviour of the powder compact. The disintegration process is specifically critical for immediate-release dosage forms. Its mechanisms and the factors impacting disintegration are discussed and methods used to study the disintegration in-situ are presented. This review further summarises mathematical models used to simulate disintegration phenomena and to predict drug release kinetics.

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Drug Delivery Symposium

27th -28th June 2017

Swissôtel - Zurich, Switzerland

More Information & Online Registration

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Workshop on Oral Controlled Release - APGI 6 July 2017 in Lille, France

Lille - 6 July 2017

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How to reduce the risk of tablet picking and sticking

Summary

Poor lubrication results in picking and sticking problems during production. These are one of the most common causes of tablet defects which result in slow running of the tablet press and reduced output. High ejection stress (>5 MPa) is strongly correlated with manufacturing problems.The effect of lubricant concentration on tabletability, tablet ejection and detachment can be evaluated using the Gamlen D series. Lubricant effectiveness rank order varies between materials; some materials are better lubricated by sodium stearyl fumarate than by magnesium stearate. Detachment (take-off) force and peak ejection force should be evaluated as potential critical quality attribute for tablets.

 

Introduction

Successful implementation of the principles of Quality by Design relies upon the capability to make accurate and reliable measurements of material properties. The critical quality attributes (CQAs) relating to tablet compression are tabletability, compressibility and compactibility. The CQAs relating to tablet lubrication are the ejection profile (peak ejection force and ejection force vs displacement profile), and the punch detachment, or take-off, force  (force required to detach the tablet from the punch). In principle these should be optimised on a product by product basis.
Ejection studies on instrumented tablet machines are normally difficult to perform because the same load cell is used for measuring compression force as is used for ejection, but ejection forces are much smaller and so hard to measure accurately. Measurement of detachment, or punch take-off force is not normally undertaken at all during laboratory evaluation.

The purpose of this work was to study the impact of blending time and lubricant concentration on ejection and detachment as a trial for QbD lubrication studies.

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Novel Uses of Pharmaceutical Polymers as enabled by KinetiSol® Dispersing

Poor water-solubility is a common characteristic of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate and bioavailability of these active ingredients belonging to BCSII and IV classifications. Over the last decade, nano-crystal delivery forms and amorphous solid dispersions have become well established in commercially available products and industry literature. Chapter 1 is a comparative analysis of these two methodologies primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with a survey of commercial relevant scientific literature. Marketed products from both technologies are presented, but there appears to be more amorphous dispersion products on the U.S. market today and current development trends are showing an industry preference for amorphous solid dispersions. 

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Biopolymer in Gene Delivery

Abstract

Nowadays, biopolymers, a class of biomaterials, represent frontier area in the drug delivery systems. Drug release from nano- and microparticles is a complex process, which involves several steps. Uptake of nanoparticle in the intracellular is affected by numerous factors. Recently, gene delivery has been considered one of the promising approaches for the treatment of various diseases acquired genetically in human being. The use of biopolymers as nanoparticles in gene delivery can potentially avoid many of the safety concerns in the gene delivery system. In gene delivery, the genetic materials such as DNA plasmids, RNA and siRNA are either encapsulated inside or conjugated to the nanoparticles, which protects the genetic materials until the drug reaches its target site. Treatment of the diseases is based on the effective delivery of the genetic materials into specific cells that are responsible for disease development. Various properties such as particle size, surface charge, morphology of the surface and release rate of the loaded molecules are the important parameters in the gene delivery system. In this chapter, various biopolymers (cationic polymers) and inorganic non-viral-delivery vectors used in gene delivery used as therapeutic agents are discussed.

Keywords: gene delivery, polymers, biopolymers, delivery system, therapeutic effect

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Microstructural effects in drug release by solid and cellular polymeric dosage forms: A comparative study

Abstract

In recent studies, we have introduced melt-processed polymeric cellular dosage forms to achieve both immediate drug release and predictable manufacture. Dosage forms ranging from minimally-porous solids to highly porous, open-cell and thin-walled structures were prepared, and the drug release characteristics investigated as the volume fraction of cells and the excipient molecular weight were varied. In the present study, the relative weight fractions of the drug and the excipient are changed over a large range and their effect on the drug release rate is investigated. Both minimally-porous solid structures and cellular dosage forms consisting of various weight fractions of Acetaminophen drug and polyethylene glycol (PEG) excipient are prepared and tested. Results of dissolution experiments show that the non-porous dosage forms disintegrate and release drug by slow surface erosion, and the erosion rate and specific drug release rate decrease as the drug weight fraction is increased. By contrast, the open-cell structures disintegrate rapidly by viscous exfoliation, and the disintegration rate is independent of drug weight fraction. Erosion models suggest that the non-porous solid dosage forms erode by convective mass transfer of the excipient if the drug volume fractions are small. At larger drug volume fractions, however, the slower-eroding drug particles hinder access of the free-flowing fluid to the excipient, thus slowing down erosion of the composite solid. The disintegration rate of the cellular dosage forms, by contrast, is limited by diffusion of the dissolution fluid into the excipient phase of the thin cell walls. Because the wall thickness is of the order of the drug particle size, the drug particles cannot hinder diffusion through the excipient across the walls, and thus the specific drug release rate is mostly unaffected by the weight fraction of drug.

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Raw Materials/ Functional Excipients Roundtable

How have advances in raw materials functionality, supply and quality affected the pharm/biopharma industry?

Jason M. LePree, PhD, Gattefossé USA, Pharmaceutical Division, Application Lab Manager: In the not too distant past, excipients were viewed as inert substances, judged mainly by their conformity to compendia.This view is not realistic. Increasingly known to the users is that excipients are actually referenced by compendia under general definitions, i.e. chemical descriptions that refer to a major component in the raw material. As a result, smaller constituents that may well contribute to the functionality of the excipient could be overlooked by the user. It is well understood that two raw materials complying with a single monograph, could have very different functionalities due to these very minor, concomitant components which are inherent to raw material source and manufacturing process.

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The tracking of interfacial interaction of amorphous solid dispersions formed by water-soluble polymer and nitrendipine

Abstract

 

Herein, interfacial interactions of amorphous solid dispersion formed by nitrendipine (TDP) and two types of water-soluble polymers (polyvinyl pyrrolidone K30 (PVP) and polyethylene glycol 6000 (PEG)) were tracked mainly concerning with interaction forces and wetting process. Infrared spectroscopy (IR), Raman spectroscopy and contact angle instrument were mainly used through the study. Hydrogen bonding forces were formed between drug and excipient in TDP-PVP and TDP-PEG. The red raman shift of TDP-PVP and TDP-PEG confirmed the hydrogen bonding forces between TDP and the two polymers. Both TDP-PVP and TDP-PEG showed higher drug release and TDP-PVP accomplished TDP release faster due to its better drug amorphous state. It is believed that the track of interfacial interactions will certainly become powerful tools to provide valuable instruction for designing and evaluating amorphous solid dispersions.

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Continuous Heterogeneous Crystallization on Excipient Surfaces

A novel continuous heterogeneous crystallization process is developed in which the active pharmaceutical ingredient (API) is crystallized directly on the surface of an excipient within the crystallizer. The product is subsequently dried and formed into tablets without the need for complex downstream processing steps, such as milling, sieving, granulation, and blending. The aim is to eliminate many steps of the particle processing in drug product manufacturing. The APIs and excipients systems were selected by investigating heteroepitaxial mechanisms. The effects of various process parameters, such as temperature, residence time, and mode of operation, on drug loading were studied. Three different process designs—mixed suspension mixed product removal with a traditional impeller, Viscojet mixing, and a fluidized bed crystallizer—were utilized for direct crystallization of the API on the surface of the crystalline excipient. The excipient selection and process design parameters have a significant impact on drug loading, avoidance of bulk nucleation and crystallization, control of API crystal shape and size, and process control. The maximum drug loading of the excipient with API in this study was 47%. Also, it was demonstrated that increasing the supersaturation ratio and residence time increased the drug loading. The products were collected from the crystallizer and directly compressed into tablet form. The tablet hardness and dissolution profile were also studied. The fully continuous process eliminates the downstream steps, resulting in the production of crystalline compounds and the final form (tablets) in a significantly faster, more efficient, and more economical manner with a smaller footprint.

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Optimization and in-vitro Evaluation of Poly (lactic acid) /Mesalazine Microspheres as Drug Carriers

ABSTRACT

Purpose: The present study is intended to the preparation and optimization of controlled drug release microparticles based on polylactic acid and Mesalazine. This active ingredient is usually used in the therapy of intestine in ammatory diseases, particularly the Crohn’s disease and hemorrhagic recto colitis. Methods: Microencapsulation by simple O/W emulsion solvent evaporation method was used to prepare these formulations. Some of the process variables such as the emulsi er concentration, the polymer concentration, the drug: polymer ratio and stirring speed were varied and the obtained biodegradable microparticles were characterized by FTIR spectroscopy, X-ray diffraction, DSC method and optical microscopy. The drug release was established both in simulated intestinal  uid and distilled water and the data analysis and the release mechanism were investigated on the basis of Higuchi and Korsmeyer-Peppas models. Results: The microparticles’ size i.e. the number mean diameter (d10) ranged from 127 to 744 μm and the drug content varied from 12 to 27%. The effect of the selected variables on the microparticles’ characteristics (size, morphology and drug release) were exhaustively discussed for the PLA/mesalazine microparticles’ optimization. Conclusion: This study showed that the microparticles’ morphology depended strongly on the emulsi er concentration and the drug entrapment is related to the initial drug:polymer ratio and polymer concentration.

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