Using United States Pharmacopeia Research Articles

Stability and Compatibility of an Intramuscular Fetal Anesthetic Cocktail for Fetal Intervention

Introduction: The aim of the study was to evaluate chemical stability and physical compatibility when combining fentanyl, rocuronium, and atropine in a fixed ratio to support intramuscular drug delivery during fetal intervention and surgery. Methods: A highly concentrated combination of fentanyl, rocuronium, and atropine was created based on common prescribing practices at a maternal-fetal care center. Chemical stability testing was completed using liquid chromatograph mass spectrometry-mass spectrometry (LC/MS-MS) to detect and quantitate atropine, rocuronium, and fentanyl, with fentanyl-d5 being an internal standard at 6, 12, 24, and 36 h following sample preparation. Physical compatibility testing was completed using United States Pharmacopeia (USP) <788> recommended analytical technique of light obscuration in addition to novel backgrounded membrane imaging at 6 and 24 h following sample preparation. Physical compatibility was determined using USP <788> particle count limits for both techniques. Results: Based on LC/MS-MS results, the samples retained expected medication concentrations at all time points tested. For physical compatibility testing, the particle counts met criteria to be considered compatible per USP <788> large-volume particle count thresholds at 6 h by both methods but exceeded tolerable thresholds at 24 h. Discussion/Conclusion: The combination of rocuronium, fentanyl, and atropine for intramuscular fetal administration is physically compatible and chemically stable for 6 h.

Design and development of 3D-printed bento box model for controlled drug release of propranolol HCl following pharmacopeia dissolution guidelines

The goal of this study was to develop a 3D-printed bento box model (3D-printed BB) with one or two chambers containing propranolol hydrochloride (PNL) as powder and matrix tablet for controlled drug release at varying times using United States Pharmacopeia (USP) dissolution guidelines. The 3D-printed BBs were made with commercial polyvinyl alcohol filament and a fused deposition modeling (FDM) 3D printer, with varying infill percentages and wall thicknesses. The physicochemical properties of the 3D-printed BBs, including appearance, thickness, size, weight, hardness, swelling, and erosion properties were investigated. The surface and cross-section morphologies of the 3D-printed BBs were characterized using a FESEM. According to FESEM images, the different infill percentages had a significant effect on the internal structure of the 3D-printed BBs’ caps, but a minor effect on the internal structure of their walls. PNL release from the 3D-printed BB began in a pH 1.2 medium, followed by drug release in a pH 6.8 medium. Some formulations of 3D-printed BB could achieve a drug release percentage within all the ranges specified by USP dissolution guidelines. 3D-printed BBs, therefore, have the potential to revolutionize the future of the pharmaceutical industry by facilitating control of the amount of drugs released at predetermined intervals.

On Absorption Modeling and Food Effect Prediction of Rivaroxaban, a BCS II Drug Orally Administered as an Immediate-Release Tablet.

The present work evaluates the food effect on the absorption of rivaroxaban (Riva), a BCS II drug, from the orally administered commercial immediate-release tablet (Xarelto IR) using physiologically based pharmacokinetic (PBPK) and conventional in vitro–in vivo correlation (IVIVC) models. The bioavailability of Riva upon oral administration of Xarelto IR tablet is reported to exhibit a positive food effect. The PBPK model for Riva was developed and verified using the previously reported in vivo data for oral solution (5 and 10 mg) and Xarelto IR tablet (5 and 10 mg dose strength). Once the PBPK model was established, the in vivo performance of the tablet formulation with the higher dose strength (Xarelto IR tablet 20 mg in fasted and fed state) was predicted using the experimentally obtained data of in vitro permeability, biorelevant solubility and in vitro dynamic dissolution data using United States Pharmacopeia (USP) IV flow-through cell apparatus. In addition, the mathematical IVIVC model was developed using the in vitro dissolution and in vivo profile of 20 mg strength Xarelto IR tablet in fasted condition. Using the developed IVIVC model, the pharmacokinetic (PK) profile of the Xarelto IR tablet in fed condition was predicted and compared with the PK parameters obtained via the PBPK model. A virtual in vivo PK study was designed using a single-dose, 3-treatment cross-over trial in 50 subjects to predict the PK profile of the Xarelto® IR tablet in the fed state. Overall, the results obtained from the IVIVC model were found to be comparable with those from the PBPK model. The outcome from both models pointed to the positive food effect on the in vivo profile of the Riva. The developed models thus can be effectively extended to establish bioequivalence for the marketed and novel complex formulations of Riva such as amorphous solid dispersions.

Enhancement of the solubility and the dissolution rate of oral nimodipine formulation with solid dispersion

The present study was an attempt to enhance the dissolution rate of nimodipine (a poorly water-soluble drug), The objective of this study was to evaluate poloxamer 407 as a carrier for nimodipine solid dispersions. The solid dispersions of nimodipine with poloxamer 407 were prepared by the hot melting technique, the molar ratio (3:1). The physicochemical properties of Solid dispersion were investigated by Differential Scanning Calorimetry (DSC), powder x-ray diffraction (PXRD), and Fourier Transform Infrared (FT-IR) spectroscopy. The FT-IR spectra indicated there was no chemical interaction between nimodipine and poloxamer 407 in the solid dispersion. DSC analysis indicated a decrease in the melting point of nimodipine and poloxamer 407 in solid dispersion. The tablet form was prepared by wet granulation of nimodipine with a binder solution of poloxamer 407 and compressed the dried granules of nimodipine into non-friable, stable tablets. The other objective, the performance of two classes of super disintegrates as croscarmellose sodium (Ac-Di-Sol), and polyvinyl pyrrolidone K30 in the dissolution of nimodipine immediate release and promoting disintegration tablets was evaluated. The in-vitro dissolution was determined by using United States Pharmacopeia (USP) type II dissolution test apparatus. All the results indicated that enhancement of the dissolution rate of nimodipine has been done successfully and drug release Kinetics indicated that the drug dissolution was a diffusion equation.

Involving Students in the Distributed Pharmaceutical Analysis Laboratory: A Citizen-Science Project to Evaluate Global Medicine Quality.

The distributed pharmaceutical analysis laboratory (DPAL) is a collaboration between 30 academic institutions around the world, whose goal is to determine the quality of medicines collected from partner organizations in low- and middle-income countries (LMICs). Institutions complete system suitability for a high-performance liquid chromatography (HPLC) system using United States Pharmacopeia (USP)-traceable reference standards, and are then approved to analyze batches of samples that are collected in LMICs by covert shoppers. Open Science Framework (OSF) allows DPAL participants access to resources for the program including an HPLC methodology manual, a wiki with HPLC troubleshooting information, detailed checklists and Excel templates for system suitability and sample assay, as well as steps for reporting results. Participants incorporate the DPAL program into their academic curriculum as undergraduate research or via lab activities for analytical chemistry or instrumental analysis courses. Over a thousand samples have been analyzed through DPAL in the last three years, and 168 samples with quality problems have been discovered, including falsified acetaminophen, adulterated amoxicillin-clavulanate and doxycycline, and substandard losartan. These quality problems are reported to the medicine regulatory agencies in the countries of origin and the WHO Rapid Alert System for further action. This real-world program gives students a hands-on opportunity to see the importance of analytical metrics taught in the classroom.

An Artificial Neural Network Approach to Predict the Effects of Formulation and Process Variables on Prednisone Release from a Multipartite System.

The impact of formulation and process variables on the in-vitro release of prednisone from a multiple-unit pellet system was investigated. Box-Behnken Response Surface Methodology (RSM) was used to generate multivariate experiments. The extrusion-spheronization method was used to produce pellets and dissolution studies were performed using United States Pharmacopoeia (USP) Apparatus 2 as described in USP XXIV. Analysis of dissolution test samples was performed using a reversed-phase high-performance liquid chromatography (RP-HPLC) method. Four formulation and process variables viz., microcrystalline cellulose concentration, sodium starch glycolate concentration, spheronization time and extrusion speed were investigated and drug release, aspect ratio and yield were monitored for the trained artificial neural networks (ANN). To achieve accurate prediction, data generated from experimentation were used to train a multi-layer perceptron (MLP) using back propagation (BP) and the Broyden-Fletcher-Goldfarb-Shanno (BFGS) 57 training algorithm until a satisfactory value of root mean square error (RMSE) was observed. The study revealed that the in-vitro release profile of prednisone was significantly impacted by microcrystalline cellulose concentration and sodium starch glycolate concentration. Increasing microcrystalline cellulose concentration retarded dissolution rate whereas increasing sodium starch glycolate concentration improved dissolution rate. Spheronization time and extrusion speed had minimal impact on prednisone release but had a significant impact on extrudate and pellet quality. This work demonstrated that RSM can be successfully used concurrently with ANN for dosage form manufacture to permit the exploration of experimental regions that are omitted when using RSM alone.

Characterization, formulation and evaluation of glibenclamide with β-cyclodextrin inclusion complexes tablets

Background: Glibenclamide is an oral antidiabetic drug which is practically insoluble in water. Formation of s-cyclodextrin inclusion complex was able to increase glibenclamide solubility. Objective: Aims of this study are to characterize, formulate and evaluate inclusion complex tablets of glibenclamide to meet the requirements in Pharmacopeia. Methods: Inclusion complex was prepared in a 1: 1 and 1: 2 molar ratio by spray drying method. Characterization were performed by using Fourier Transform Infrared (FTIR) spectroscopy and Scanning Electron Microscope (SEM). Further, it was formulated into tablets by direct compression technique using primojel and crospovidone as disintegrants. Uniformity weight, hardness, friability, disintegration, and tablets were evaluated include dissolution. Dissolution studies of inclusion complex were performed by using United States Pharmacopeia (USP) II apparatus. Drug concentration dissolution was determined with high pressure liquid chromatography (HPLC). Results: Result of FTIR and SEM provided evidence of glibenclamide and s-cyclodextrin complex formation after using spray drying methods. The tablet evaluation with primojel and crospovidone as disintegrant showed that increase concentration of disintegrant would increase disintegration time of the tablets. All of the formulas meet the requirements in the Pharmacopoeia. Conclusion: The inclusion complex of glibenclamide–s cyclodextrin successfully used for enhancing the solubility of glibenclamide. The tablets meet the requirements in Pharmacopeia.

Comparison of the composition and in vitro activity of polymyxin B products

A number of companies manufacture polymyxin B using United States Pharmacopeia (USP) metrics, rather than chemical composition, to report biological activity. Given that polymyxin B contains several different components, it is unknown whether pharmacokinetic and pharmacodynamic variability exists between the different brands and whether USP metrics capture this variability. Here we investigated the composition of polymyxin B obtained from four manufacturers (Sigma-Aldrich, AK Scientific, USP and MP Biomedicals) and evaluated their rate and extent of killing against multidrug-resistant Acinetobacter baumannii and Klebsiella pneumoniae using in vitro static time-kill experiments. Ultraviolet (UV) fingerprinting and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed similarities and differences between component distributions. The significant differences between products, based on UV fingerprinting and LC-MS/MS, did not translate into pharmacodynamic differences at the three concentrations evaluated. The aggregate polymyxin B concentration, rather than that of the individual components, influences overall bacterial killing.

A Financial Evaluation of the Centralized Repackaging of Intracameral Moxifloxacin for Cataract Surgery and Its Impact on Cost Reduction.

Background: Extensive evidence-based literature supports the use of intracameral (IC) moxifloxacin for the prevention of postoperative endophthalmitis after cataract surgery. The Aurora Pharmacy Packaging Center (APPC) has developed a process for centrally preparing IC moxifloxacin. Purpose: The aim of this study was to evaluate the centralized preparation of IC moxifloxacin production for quality assurance and to quantify a potential reduction in costs. Methods: The APPC's compounding procedure of IC moxifloxacin was evaluated using United States Pharmacopeia (USP) Convention 797 standard and compared with practices described in evidence-based literature. Patients who received IC moxifloxacin intraoperatively from one of 3 ophthalmologists during cataract surgery performed between February 15, 2016, and August 15, 2016, were identified using electronic health records. Cost savings were calculated by reviewing costs associated with drug supplies used by the APPC. Results: The APPC process for the centralized preparation of IC moxifloxacin was deemed compliant with USP 797's sterile compounding standards. USP 797 validation criteria included proper sterile technique, equipment, room sterility and pressure, beyond use dating, and storage. Implementation of the centralized production of moxifloxacin reduced the direct product cost per surgery from $140 to $20 (a cost savings of $120 per surgery). There were 459 cataract surgeries analyzed during the study period, resulting in a savings of $55 080 over 6 months. Conclusion: The APPC's centralized compounding procedure was found to be compliant with pharmacy compounding standards and to yield significant cost savings.

A Multiparticulate Delivery System for Potential Colonic Targeting Using Bovine Serum Albumin as a Model Protein : Theme: Formulation and Manufacturing of Solid Dosage Forms Guest Editors: Tony Zhou and Tonglei Li.

There are many important diseases whose treatment could be improved by delivering a therapeutic protein to the colon, for example, Clostridium difficile infection, ulcerative colitis and Crohn's Disease. The goal of this project was to investigate the feasibility of colonic delivery of proteins using multiparticulate beads. In this work, bovine serum albumin (BSA) was adopted as a model protein. BSA was spray layered onto beads, followed by coating of an enteric polymer EUDRAGIT® FS 30 D to develop a colonic delivery system. The secondary and tertiary structure change and aggregation of BSA during spray layering process was examined. The BSA layered beads were then challenged in an accelerated stability study using International Council for Harmonization (ICH) conditions. The in vitro release of BSA from enteric coated beads was examined using United States Pharmacopeia (USP) dissolution apparatus 1. No significant changes in the secondary and tertiary structure or aggregation profile of BSA were observed after the spray layering process. Degradation of BSA to different extents was detected after storing at 25°C and 40°C for 38days. Enteric coated BSA beads were intact in acidic media while released BSA in pH7.4 phosphate buffer. We showed the feasibility of delivering proteins to colon in vitro using multiparticulate system.

Design and Optimization of Controlled Drug Delivery System of Losartan Potassium

Purpose : The objective of the study was to develop microspheres of Losartan potassium as controlled drug delivery system by using various polymer (HPMC and Ethylcellulose), evaluating the relationship and influence of different content levels of HPMC, and Ethylcellulose, in order to achieve a zero order release of Losartan potassium. Approach : Microspheres were prepared by solvent evaporation process. Release kinetics was evaluated by using United States Pharmacopoeia (USP) type I dissolution apparatus. The release mechanism of microspheres loaded with Losartan potassium was determined by fitting the data in Korsmeryer peppas equation. The regression coefficient values for Peppas model was found to be high, indicating adequate fitting. The 'n' value was ranged from 0.548 to 0.963 indicating Non Fickian diffusion for all the formulations. Optimization was performed by using desirability function. To validate the model, the optimized formula was subjected to in vitro characterization. Findings : Release kinetics of Losartan potassium from these microspheres was principally regulated by HPMC K4M and Ethylcellulose. Percentage yield, entrapment efficiency and particle size of optimized formula was found to be 91.42%, 68.01% and 310μm. Formulation (F1) release at the end of 12 hours of dissolution studies was found to be 79.81%. Conclusion : It can be concluded that Losartan potassium loaded microspheres could be successfully formulated by using HPMC 4KM and Ethylcellulose by solvent evaporation method to obtain maximum percentage yield, entrapment efficiency, desired particle size.

Formulation and Evaluation of Gastro Retentive Matrix Tablets of Sitagliptin

The present investigation concerns the formulation and evaluation of gastro retentive matrix tablets of sitagliptin which after oral administration, are designed to prolong the gastric residence time, increase drug bioavailability and sustain the drug release. The tablets were prepared by using various polymers viz; HPMC (K4M, K15 M, K100M), xanthan gum and combination of polymers and sodium bicarbonate. The tablets were prepared by wet granulation method and further evaluated for pre compression parameters, physical characteristics, in vitro release, buoyancy time, lag-time and swelling index. Formulations were evaluated for in vitro buoyancy and drug release study using United States Pharmacopeia (USP) 23 paddle-type dissolution apparatus using 0.1 N HCl (pH 1.2) as a dissolution medium. All formulations had floating lag times below 3 minutes and constantly floated on dissolution medium for more than 12 hrs. The optimized formulations (F13) were subjected to various kinetic release investigations and it was found that the mechanism of drug release was predominantly diffusion in combination with polymeric relaxation. The best formulation (F13) remained buoyant and showed a sustained drug release (98%) for 12hrs. F13 showed no significant change in physical appearance, drug content or floating lag time after storage at 45°C/75% RH for three months.

Enhancement of Solubility of Lamotrigine by Solid Dispersion and Development of Orally Disintegrating Tablets Using 3(2) Full Factorial Design.

Present investigation deals with the preparation and evaluation of orally disintegrating tablets (ODTs) of lamotrigine using β-cyclodextrin and PVP-K30 as polymers for the preparation of solid dispersion which help in enhancement of aqueous solubility of this BCS CLASS-II drug and sodium starch glycolate (SSG) and crospovidone as a superdisintegrating agent, to reduce disintegration time. The ODTs were prepared by direct compression method. Nine formulations were developed with different ratios of superdisintegrating agents. All the formulations were evaluated for disintegration time, weight variation, hardness, friability, drug content uniformity, wetting time, and in vitro drug release study. In vitro drug release study was performed using United States Pharmacopoeia (USP) type 2 dissolution test apparatus employing paddle stirrer at 50 rpm using 900 mL of 0.1 N HCl maintained at 37°C ± 0.5°C as the dissolution medium. On the basis of evaluation parameters formulations were prepared using β-CD 1 : 1 solid dispersion. Then 32 full factorial design was applied using SSG and crospovidone in different ratios suggested by using design expert 8.0.7.1 and optimized formulation was prepared using amount of SSG and crospovidone as suggested by the software. The optimized formulation prepared had disintegrating time of 15 s, wetting time of 24 s, and % friability of 0.55.

Formulation and Evaluation of Extended Release Matrix Tablet of Zidovudine Using Hydrophilic and Hydrophobic Matrix Formers

Abstract: Background: Zidovudine is a virustatic drug has a very short half life and undergoes consider¬able first-pass metabolism thus necessitating an adequate zero order delivery. Objectives: The aim of the present study was to prepare and characterize extended release matrix tablets of Zidovudine (ZID) using hydrophilic (HPMC K4M) and hydrophobic olibanum gum resin polymers separately. Methods: The matrix forming resin was extracted from a naturally available olibanum gum and evaluated as a matrix former. The FTIR and DSC studies confirmed that no chemical interaction took place in the final formulations. The scanning electron microscopy was used to visualize the effect of dissolution medium on matrix tablet surface. Release kinetics was evaluated by using United States Pharmacopoeia (USP)-23 type I dissolution apparatus. Results: The in-vitro drug release study of formulation with HPMC K4M revealed that the controlled release was only for 12 h. The effect of polymeric resin on release profile of drug from matrix tablet was slow over 24 h. Drug release was by non-fickian diffusion mechanism. Resin encapsulated matrix tablet of ZID exhibited good controlled release characteristics and were found suitable for once a day oral controlled release products. Fitting the in-vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release. Conclusion: In conclusion, the results suggest that the developed controlled release tablets of ZID with olibanum resin matrix could perform therapeutically better than tablets prepared with HPMC K4M, leading to improved efficacy and better patient compliance. Key words: Olibanum gum resin, matrix tablet, controlled release, zidovudine.

Preparation and Characterization of Phytosomal-Phospholipid Complex of P. Amarus and its Tablet Formulation

Present investigation was aimed at formulation, characterization and evaluation of phytosomal complex tablets for sustained delivery of Phyllanthus amarus complex. Phyllanthin, one of the active lignin present in this plant species was isolated from the aerial parts, by silica gel column chromatography employing gradient elution with hexane −ethyl acetate solvent mixture. It was obtained in high yields (1.23%), compared to reported procedures and the purity was ascertained by HPTLC analysis. Phyllanthin was characterized for M.P, UV −Visible spectrophotometry, FT-IR, 1H NMR, 13C and NMR analysis. Release kinetics was evaluated by using United States Pharmacopeia (USP)-22 type I dissolution apparatus. Scanning electron microscopy was used to visualize the effect of dissolution medium on matrix tablet surface. HPTLC was carried out for quantitative and qualitative estimation of Phyllanthin in Phyllanthus amarus and Rf of phyllanthin was found to be about 0.25. The content was found to be maximum for phytosomal complex of phyllanthus formed by vaccum drying of 1:1 drug excipient ratio. The in-vitro drug release study revealed that optimized formulation sustained the drug release for 12 hr (88.1% ± 4.1% release). Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.

Formulation Development and in vitro Evaluation of Drug Release Kinetics from Sustained Release Aceclofenac Matrix Tablets using Hydroxypropyl Methyl Cellulose

The objective of the present study was to develop a once-daily sustained release matrix tablet of Aceclofenac using hydroxypropyl methyl cellulose (Methocel K 100M CR) as release controlling factor and to evaluate drug release parameters as per various release kinetic models. The tablets were prepared by direct compression method. The powder blends were evaluated for angle of repose, loose bulk density, tapped bulk density, compressibility index, total porosity and drug content etc. The tablets were subjected to thickness, weight variation test, drug content, hardness, friability and in vitro release studies. The in vitro dissolution study was carried out for 24 hours using United States Pharmacopoeia (USP) 22 paddle-type dissolution apparatus in phosphate buffer (pH 7.4). The powder blends showed satisfactory flow properties, compressibility index and drug content etc. All the tablet formulations showed acceptable pharmacotechnical properties and complied with pharmacopoeial specifications. The results of dissolution studies indicated that the formulation F-3 (40% Methocel K100M CR of total weight of tablet) could extend the drug release up to 24 hours and the total release pattern was very close to the theoretical release profile. By comparing the dissolution profiles with the originator brand of Arrestin SR, the formulation F-3 exhibited drug release profile like originator brand. From this study, a decrease in release kinetics of the drug was observed by increasing the polymer concentration. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport, which was only dependent on the type and amount of polymer used. The drug release followed both diffusion and erosion mechanism in all cases. The drug release from the formulation (F-3) was satisfactory after 3 months storage in 400C and 75% RH. Besides, this study explored both of the optimum concentration and effect of polymer(s) on Aceclofenac release pattern from the tablet matrix for 24 hour period. The matrix tablet of Aceclofenac using HPMC with molecular weight of K100M controlled the drug release effectively for 24 hours; hence the formulation can be considered as a once daily sustained release tablet of Aceclofenac in order to improve patient compliance. DOI: http://dx.doi.org/10.3329/dujps.v11i1.12485 Dhaka Univ. J. Pharm. Sci. 11(1): 37-43, 2012 (June)

Development and in vitro Evaluation of Sustained Release Matrix Tablets of Indapamide from Methocel® K15 MCR and K100 LVCR

Indapamide, a low-dose thiazide-type diuretic, is used for the treatment of essential hypertension. In this study, we developed an indapamide sustained release formulation using Methocel K15 MCR (a modified hydroxypropyl methylcellulose), Methocel K100 LVCR (a modified hydroxypropyl methylcellulose), magnesium stearate, talc and starch 1500 by direct compression. The powders for tableting were evaluated for angle of repose, loose bulk density, tapped bulk density, compressibility index, total porosity etc. The tablets were subjected to thickness, weight variation test, hardness, friability and in vitro release studies. The in vitro dissolution study was carried out in the gastric medium (pH 1.3) for first two hours and then in the intestinal medium (pH 6.8) for 22 hours using United States Pharmacopoeia (USP) 22 paddle-type dissolution apparatus. The granules showed satisfactory flow properties, compressibility index etc. All the tablets complied with pharmacopoeial specifications. The results of dissolution studies indicated that the formulation F-5 and F-7 (up to 75.36 % drug release in 12 hours) could extend the drug release up to 12 hours. The drug release patterns were simulated in different kinetic orders such as Zero Order release kinetics, First Order release kinetics, Higuchi release kinetics, Korsmeyer-Peppas release kinetics and Hixson-Crowell release kinetics to assess the release mechanism. From the study we observed that Higuchi release kinetics was the predominant release mechanism than Zero Order and First Order kinetics. The drug release mechanism from the matrix tablets was found to be non Fickian mechanism. DOI: http://dx.doi.org/10.3329/dujps.v10i2.11785 Dhaka Univ. J. Pharm. Sci. 10(2): 87-92, 2011 (December)

Accelerated in-vitro release testing methods for extended-release parenteral dosage forms

This review highlights current methods and strategies for accelerated in-vitro drug release testing of extended-release parenteral dosage forms such as polymeric microparticulate systems, lipid microparticulate systems, in-situ depot-forming systems and implants. Extended-release parenteral dosage forms are typically designed to maintain the effective drug concentration over periods of weeks, months or even years. Consequently, 'real-time' in-vitro release tests for these dosage forms are often run over a long time period. Accelerated in-vitro release methods can provide rapid evaluation and therefore are desirable for quality control purposes. To this end, different accelerated in-vitro release methods using United States Pharmacopeia (USP) apparatus have been developed. Different mechanisms of accelerating drug release from extended-release parenteral dosage forms, along with the accelerated in-vitro release testing methods currently employed are discussed. Accelerated in-vitro release testing methods with good discriminatory ability are critical for quality control of extended-release parenteral products. Methods that can be used in the development of in-vitro-in-vivo correlation (IVIVC) are desirable; however, for complex parenteral products this may not always be achievable.

Accelerated in vitro release testing of implantable PLGA microsphere/PVA hydrogel composite coatings

Dexamethasone loaded poly(lactic-co-glycolic acid) (PLGA) microsphere/PVA hydrogel composites have been investigated as an outer drug-eluting coating for implantable devices such as glucose sensors to counter negative tissue responses to implants. The objective of this study was to develop a discriminatory, accelerated in vitro release testing method for this drug-eluting coating using United States Pharmacopeia (USP) apparatus 4. Polymer degradation and drug release kinetics were investigated under “real-time” and accelerated conditions ( i.e. extreme pH, hydro-alcoholic solutions and elevated temperatures). Compared to “real-time” conditions, the initial burst and lag phases were similar using hydro-alcoholic solutions and extreme pH conditions, while the secondary apparent zero-order release phase was slightly accelerated. Elevated temperatures resulted in a significant acceleration of dexamethasone release. The accelerated release data were able to predict “real-time” release when applying the Arrhenius equation. Microsphere batches with faster and slower release profiles were investigated under “real-time” and elevated temperature (60 °C) conditions to determine the discriminatory ability of the method. The results demonstrated both the feasibility and the discriminatory ability of this USP apparatus 4 method for in vitro release testing of drug loaded PLGA microsphere/PVA hydrogel composites. This method may be appropriate for similar drug/device combination products and drug delivery systems.

Properties of Gastroretentive Sustained Release Tablets Prepared by Combination of Melt/Sublimation Actions of L-Menthol and Penetration of Molten Polymers into Tablets

A novel floating sustained release tablet having a cavity in the center was developed by utilizing the physicochemical properties of L-menthol and the penetration of molten hydrophobic polymer into tablets. A dry-coated tablet containing famotidine as a model drug in outer layer was prepared with a L-menthol core by direct compression. The tablet was placed in an oven at 80°C to remove the L-menthol core from tablet. The resulting tablet was then immersed in the molten hydrophobic polymers at 90°C. The buoyancy and drug release properties of tablets were investigated using United States Pharmacopeia (USP) 32 Apparatus 2 (paddle 100 rpm) and 900 ml of 0.01 N HCl. The L-menthol core in tablets disappeared completely through pathways in the outer layer with no drug outflows when placed in an oven for 90 min, resulting in a formation of a hollow tablet. The hollow tablets floated on the dissolution media for a short time and the drug release was rapid due to the disintegration of tablet. When the hollow tablets were immersed in molten hydrophobic polymers for 1 min, the rapid drug release was drastically retarded due to a formation of wax matrices within the shell of tablets and the tablets floated on the media for at least 6 h. When Lubri wax® was used as a polymer, the tablets showed the slowest sustained release. On the other hand, faster sustained release properties were obtained by using glyceryl monostearate (GMS) due to its low hydrophobic nature. The results obtained in this study suggested that the drug release rate from floating tablets could be controlled by both the choice of hydrophobic polymer and the combined use of hydrophobic polymers.