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The focus of the present work was to develop co-amorphous dispersion (CAD) formulations of tacrolimus (TAC) using sucrose acetate isobutyrate as a carrier, evaluate by in vitro and in vivo methods and compare its performance with hydroxypropyl methylcellulose (HPMC) based amorphous solid dispersion (ASD) formulation. CAD and ASD formulations were prepared by solvent evaporation method followed by characterization by Fourier transformed infrared spectroscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dissolution, stability, and pharmacokinetics. XRPD and DSC indicated amorphous phase transformation of the drug in the CAD and ASD formulations, and dissolved more than 85% of the drug in 90 min. No drug crystallization was observed in the thermogram and diffractogram of the formulations after storage at 25 °C/60% RH and 40 °C/75% RH. No significant change in the dissolution profile was observed after and before storage. SAIB-based CAD and HPMC-based ASD formulations were bioequivalent as they met 90% confidence of 90–11.1% for Cmax and AUC. The CAD and ASD formulations exhibited Cmax and AUC 1.7–1.8 and 1.5–1.8 folds of tablet formulations containing the drug's crystalline phase. In conclusion, the stability, dissolution, and pharmacokinetic performance of SAIB-based CAD and HPMC-based ASD formulations were similar, and thus clinical performance would be similar. [ABSTRACT FROM AUTHOR]

Palatability of a formulation is one of the primary requirements for therapeutic compliance in children. Clindamycin (CLN) often prescribed to children to treat various infections. However, it has a bitter taste and bad smell. The focus of the present investigation was to develop salt of CLN with a commonly used sweetener such as cyclamic acid (CYA) to improve the palatability. The salt forms were prepared by solubilization crystallization method and characterized by Fourier transformed infrared (FTIR), Near infrared (NIR), Raman, X-ray powder diffraction, scanning electron microscopy, solubility, dissolution, and solid-state physical and chemical stability at 25 °C/60% RH and 40 °C/75% RH for 1 month and 60 °C for 2 weeks. Spectroscopic and diffraction data indicated the formation of a new solid phase, which was different from hydrochloride salt of CLN. Shape of crystal was rectangular prism. Stoichiometric ratio between CLN and CYA in the new salt CLN-CYA was 1:1 and its melting point was 85.6 °C. There was a 2.4-fold reduction in solubility of CLN-CYA at pH 4 compared with CLN-HCl. Moreover, the dissolution rate and extent were similar between the two salts and meeting USP requirement of 85% dissolution in 30 min. Salt was physically and chemically stable at 60 °C, 25 °C/60% RH, and 40 °C/75% RH conditions but hygroscopic at high humidity condition. In conclusion, new salt will provide a new avenue for the development of a palatable formulation of CLN. [ABSTRACT FROM AUTHOR]

Abstract: The focus of present research was to understand and control the variability of solid dispersion (SD) formulation of non-ribosomal peptide antibiotic, vancomycin (VCM). Hunter screening design was constructed using seven independent variables namely melting temperature (X 1), congealing temperature (X 2), mixing time (X 3), type of capsule shell (X 4), filling method (X 5), molecular weight of polyethylene glycol (PEG, X 6) and surfactant type (X 7), and responses measured were cumulative percentage of VCM released in 45min (Y 1) and potency (Y 2). The SD formulations were prepared by melt-fusion method, and tested for dissolution, potency, and characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and near infrared chemical imaging (NIR-CI). Statistically significant (p <0.05) effect of congealing temperature (X 2), type of capsule shell (X 4), filling method (X 5), molecular weight of PEG (X 6) was revealed on Y 1, and R 2 of 0.992 was obtained between experimental and predicted value. None of the factors have statistically significant (p >0.05) influence on Y 2. SEM, DSC and PXRD indicated crystalline nature of SD formulations. Homogeneity of SD formulations was shown by NIR-CI images. In summary, the quality of VCM SD formulations could be assured by controlling the critical factors during manufacturing. [Copyright &y& Elsevier]

The objectives of the present study were to (1) optimize the release rate of insulin from compressed microparticulates and (2) compare the in vivo hypoglycemic effect of optimized insulin microparticulates with compressed enzyme inhibitor (duck ovomucoid) and without inhibitor. A 3-factor, 15-run Box Behnken design was used to construct polynomial models correlating the dependent and independent variables. Independent processing variables were rate of addition of the alcoholic Eudragit© L100 dispersion, volume of the antisolvent, and compression pressure. Responses were cumulative percent of insulin released from 1-6 hours. Insulin and ovomucoid release was simultaneously analyzed by high-performance liquid chromatography. They demonstrated variable release rates, which were optimized to the Higuchi's square root of time model to release the insulin and the inhibitor over 6 hours. The relationship between dissolution profiles and process parameters were demonstrated by contour and response surface plots. In vivo hypoglycemic effect was evaluated in rabbits in a 3-way crossover design. Cocompressed microparticulates of insulin and duck ovomucoid displayed a 3.2-fold greater hypoglycemic effect when compared with a similar preparation without ovomucoid. This study demonstrated the potential benefits of dosage forms with dual controlled-release mechanisms for both the protein and enzyme inhibitor. [ABSTRACT FROM AUTHOR]

An important aspect of the ''Desired State'' of manufacturablity as defined by the International Committee of Harmonization is the mechanistic understanding and predictability of dosage forms at the laboratory scale. The accomplishment of that aspect is often preceded by a formulation knowledge and previous history of the project or by screening of the variables to identify the critical ones. Osmotically controlled drug delivery systems provide a means of eliminating the effect of pH, food as well as transit time on drug release. Salmon calcitonin, a hypocalcemic peptide, was formulated as an osmotically controlled bilayered enteric-coated dosage form with turkey ovomucoid (enzyme inhibitor) and glycyrrhetinic acid (permeation enhancer) along with other excipients. Drug release from the dosage form is generally affected by formulation and process variables. However, the literature information is very limited for the effects of these variables on the release kinetics of peptide drugs from osmotically controlled systems. The objective of this study was to evaluate the factors that influence the release of the drug from bilayered, osmotically controlled tablets coated with a semipermeable membrane of cellulose acetate. A seven-factor- 12-run Plackett-Burman screening technique was employed to evaluate the effects of orifice size, coating level, amounts of sodium chloride, Polyox® N10 and N80 and Carbopol® 934P and 974P on drug release. Response variables was cumulative percent released in 24 hr with constraints on time for 25% and 50% drug release. Factors showing maximum influence on drug release were amounts of Carbopol® 934P and Polyox® N10 in the drug layer, orifice size and coating level showing negative effects with the main effect magnitudes of -30.85, -10.97, -9.61, and -9.95, respectively. [ABSTRACT FROM AUTHOR]

The focus of the present investigation was to develop a predictive dissolution model for tablets coated with blends of cellulose acetate butyrate (CAB) 171-15 and cellulose acetate phthalate (C-A-P) using the design of experiment and chemometric approaches. Diclofenac sodium was used as a model drug. Coating weight gain (X1, 5, 7.5 and 10%) and CAB 171-15 percentage (X2, 33.3, 50 and 66.7%) in the coating composition relative to C-A-P and were selected as independent variables by full factorial experimental design. The responses monitored were dissolution at 1 (Y1), 8 (Y2), and 24 (Y3) h. Statistically significant (p < 0.05) effects of X1 on Y1 and X2 on Y1, Y2, and Y3 were observed. The models showed a good correlation between actual and predicted values as indicated by the correlation coefficients of 0.964, 0.914, and 0.932 for Y1, Y2, and Y3, respectively. For the chemometric model development, the near infrared spectra of the coated tablets were collected, and partial least square regression (PLSR) was performed. PLSR also showed a good correlation between actual and model predicted values as indicated by correlation coefficients of 0.916, 0.964, and 0.974 for Y1, Y2, and Y3, respectively. Y1, Y2, and Y3 predicted values of the independent sample by both approaches were close to the actual values. In conclusion, it is possible to predict the dissolution of tablets coated with blends of cellulose esters by both approaches. [ABSTRACT FROM AUTHOR]

Portioned moist snuff and snus, two subcategories of smokeless tobacco products (STP) were dissolution tested as a quality control test. A USP Apparatus 4 was employed to develop and validate the method. The method was assessed based on time to reach nicotine dissolution plateau, percentage difference between two profiles at each time point, relative standard deviation (RSD), and f1 (similarity) and f2 (dissimilarity) values. Based on these criteria, 200 ml volume and 8 ml/min flow were found be discriminatory. The amount of nicotine dissolved from the nine products varied widely (2.0-3.4, 2.1-4.1, 3.3-4.6, 5.5-6.6, 6.9-9.1, 11.5-14.2, 12.5-14.6, 14.0-15.5, and 15.5-19.6 mg/pouch at 60 min). RSDs of the dissolution ranges were more than 20% at earlier time points and less than 20% at later timepoints. The developed method produced distinct profiles for all the tested products, which was further confirmed by f1 >15 and f2 <50 values. In conclusion, the developed method was discriminatory and can be employed as a quality control test and to differentiate among moist snuff and snus products. [ABSTRACT FROM AUTHOR]

The focus of present investigation was to characterize and evaluate the variability of solid dispersion ( SD) of amorphous vancomycin ( VCM), utilizing crystalline polyethylene glycol ( PEG-6000) as a carrier and subsequently, determining their percentage composition by nondestructive method of process analytical technology ( PAT) sensors. The SD were prepared by heat fusion method and characterized for physicochemical and spectral properties. Enhanced dissolution was shown by the SD formulations. Decreased crystallinity of PEG-6000 was observed indicating that the drug was present as solution and dispersed form within the polymer. The SD formulations were homogenous as shown by near infrared ( NIR) chemical imaging data. Principal component analysis ( PCA) and partial least square ( PLS) method were applied to NIR and PXRD (powder X-ray diffraction) data to develop model for quantification of drug and carrier. PLS of both data showed correlation coefficient >0.9934 with good prediction capability as revealed by smaller value of root mean square and standard error. The model based on NIR and PXRD were two folds more accurate in estimating PEG-6000 than VCM. In conclusion, the drug dissolution from the SD increased by decreasing crystallinity of PEG-6000, and the chemometric models showed usefulness of PAT sensor in estimating percentage of both VCM and PEG-600 simultaneously. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:4337-4346, 2013 [ABSTRACT FROM AUTHOR]

Abstract: The aim of present research was to design and evaluate orally disintegrating tablet (ODT) of novel lamotrigine-cyclamate salt. Box–Behnken response surface methodology was selected to design the optimized formulation. The independent factors selected were tablet hardness (X 1), disintegrant (X 2) and lubricant (X 3) levels, and responses chosen were disintegration time (DT, Y 1), friability (Y 2), T 50 (Y 3), and T 90 (Y 4). The tablets were also characterized for drug uniformity by near infrared chemical imaging (NIR-CI) and taste masking evaluation by electronic tongue. All the selected independent variables were statistically (p <0.05) effect the Y 1 while Y 2, Y 3, and Y 4 affected only by X 2. The optimized ODT was found to meet the regulatory requirement of DT and friability specification. The NIR-CI images indicated uniform distribution of active and inactive ingredients within the tablets. The electronic tongue results were analyzed by principle component analysis (PCA). It indicated that novel salt of lamotrigine and its ODT formulation have a taste similar to cyclamic acid which is indicated by close proximity on PCA score plot, lower Euclidean distance, and high discrimination index values. Furthermore, these parameters were very close to ODT placebo formulation. On the other hand, lamotrigine, its ODT, and placebo formulation were far from each other. In summary, lamotrigine salt provides another avenue for pediatric friendly formulation for children and will enhance patience compliance. [Copyright &y& Elsevier]

Nimodipine (NM) commercial formulation has been recalled due to drug crystallization in the product. Aim of present investigation was to systematically evaluate NM ternary cosolvents systems, characterize the crystallized drug and develop discriminating dissolution method that could detect the drug crystallization in the product. Mixture design was constructed using independent components namely water (X 1), glycerin (X 2) and polyethylene glycol 400 (X 3, PEG-400). Nineteen formulations were developed using various level of cosolvents mixture while drug concentration was kept constant. The response selected was the drug crystallized in the formulations kept at four storage conditions 5°C, 15°C, 25°C and 25°C/60% RH for four weeks. The crystallized drug was characterized by Fourier transformed infrared (FTIR), near infrared (NIR), NIR-chemical imaging and Raman spectroscopies, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy. Dissolution of formulation and modification was tested by USP method 2 in 0.25 and 0.50% sodium lauryl sulphate (SLS) aqueous media and run at 50 and 75rpm. X 1 promoted drug crystallization at all conditions of storage and reverse was true for X 3. Characterization data indicated that the crystallized drug in most of the formulations were modification II, but a few formulations contained significant proportion of the modification I. Dissolution in 0.25% (w/v) SLS at 75rpm was more discriminating in detecting the crystallization in the product compared to dissolution in 0.5% (w/v) SLS media. In summary, cosolvents system of NM was prone to crystallization depending upon the cosolvents composition and storage conditions. A more rational approach to develop NM formulation would entail a then through understanding of the causes of crystallization and their characterization in a variety of storage conditions. [ABSTRACT FROM AUTHOR]

The objective of the present research was to investigate application of sucrose acetate isobutyrate (SAIB) in the development of a meth-deterrent formulation in combination with polyethylene oxide (PolyoxTM) and hydroxypropyl methylcellulose. The formulations were prepared by granulating pseudoephedrine hydrochloride, hydroxypropyl methylcellulose, and PolyoxTM with an ethanolic solution of SAIB and compressed into tablets followed by heat curing. The tablets were characterized for surface morphology, crystallinity, drug distribution, hardness, particle size, extraction, and dissolution. Hardness increased insignificantly, surface morphology indicated cracking and crevices, and diffractograms showed an increase and a decrease in drug and PolyoxTM crystallinity, respectively, after heat curing. Pseudoephedrine hydrochloride, PolyoxTM, and SAIB distribution was uniform as indicated by near infrared image. The drug extraction varied from 69.5% to 77.8%, 90.3% to 106.5%, 51.3% to 81.2%, and 48.9% to 72.6% in water, ethanol, 0.1 N HCl, and 0.1 N NaOH, respectively. The dissolution was more than 85% in 9 h from all the formulations. Thus, the addition of SAIB to the formulation decreased the drug extraction in various solvents which has the potential to decrease abuse of pseudoephedrine formulation for methamphetamine synthesis. [ABSTRACT FROM AUTHOR]

The commercial product of rifaximin (RFX) contains α form. The α form can change to β form on exposure to high humidity that can occur during manufacturing, stability, and in-use period. It is critical to maintain α form of the drug in a drug product to avoid variability in clinical response. U.S. Food and Drug Administration dissolution method was found to be nondiscriminatory for RFX formulations containing either 100% α or β form. The objective of this study was to develop a discriminatory dissolution method that can detect low levels of α to β transformation in RFX products. Formulations containing a variable fraction of α and β forms were prepared by using direct compression method. Dissolution parameters investigated were type of dissolution medium (water and phosphate buffer), volume (500, 900, and 1000 mL), and paddle speed (50, 75, and 150 rpm). Dissolution in water with 0.2% sodium lauryl sulfate was less than 80% and nondiscriminatory. However, dissolution tested in a phosphate buffer pH 7.4 with 0.2% sodium lauryl sulfate at 50 rpm was discriminatory with more than 17.5% difference in dissolution profile between formulations containing α and β forms. The developed method can detect polymorphic transformation if there is 25% or more β form conversion. [ABSTRACT FROM AUTHOR]

Abstract The objective of the present study was to understand quality of brand and generic products of phenytoin sodium by in vitro methods. Three commercial products were selected for the study, 1 brand and 2 generics (product-A, product-B, and product-C). Products were repacked in pharmacy vials and stored for 12 weeks at 30°C/75% RH to simulate in-use conditions. The products were examined visually and microscopically for morphologic changes, spectroscopic and diffractometric methods for chemical changes, and dissolution, assay, and impurities for performance evaluation. Capsules content of the product-A turned yellowish to dark orange color from initial white powder, which indicated a possible chemical interaction between lactose and the drug in addition to disproportionation. This was supported by pH, microscopic, spectroscopic, and X-ray diffraction data. Product-A failed to meet United States Pharmacopoeia dissolution specification of 75% in 120 min after 2-weeks whereas product-B and product-C failed at 6-weeks of in-use stability conditions exposure. Furthermore, product-A also failed to meet United States pharmacopoeia assay and impurities specifications in 12 weeks in-use period. In summary, this study indicated salt disproportionation, chemical interactions, and phase transformations of drug and excipients in the commercial products of phenytoin sodium, which may affect the clinical performance of the product. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Phenytoin sodium (PS) is a narrow therapeutic index drug that dictates maintenance of narrow plasma concentration of the drug. This requires a good quality product that meets regulatory specifications throughout shelf-life as well as during the usage period. Quality of the drug product may change if not develop in a scientific fashion which may have ramifications on clinical outcome. The focus of the study was to understand the effect of process variables and storage conditions on the disproportionation and phase transformation of the drug, and dissolution of extended-release capsules of PS. Four formulations were prepared to contain either powder blend or granules of PS with commonly used excipients. The granules were prepared in a high shear mixture by granulating with water, ethanol or mixture thereof. The capsules were stored in pharmacy vials for 4-weeks at 40 °C/75% RH and 30 °C/65% RH. Formulations were characterized by spectroscopies (FTIR, NIR, and chemical imaging), X-ray powder diffraction (XRPD), dissolution and assay. Granules filled capsule did not meet USP dissolution specifications and there was a significant decrease in dissolution on exposure to stability conditions. Dissolution decreased from 77.56 ± 3.83% to 42.34 ± 4.31%, and 63.96 ± 6.12 to 46.53 ± 2.91 in physical mixture and water granulated formulations, respectively, after four weeks exposure at 40 °C/75% RH. Spectroscopic (NIR, FTIR, and chemical imaging) data indicated disproportionation of the drug during the storage period. Moreover, XRPD data explained a decrease in dissolution in the initial granules filled capsules as well as temperature and humidity exposed samples. It indicated the phase transformation of the drug and/or excipients, disproportionation and/or interactions. These changes further accelerated on exposure to stability conditions. In conclusion, our studies indicated the significant effect of process variables and stability conditions on the critical quality attributes of PS extended-release capsule that has the potential impact on the clinical performance of the product. [ABSTRACT FROM AUTHOR]

Understanding the impact of pharmaceutical processing, formulation excipients and their interactions on the solid-state transitions of pharmaceutical solids during use and in storage is critical in ensuring consistent product performance. This study reports the effect of polymer viscosity, diluent type, granulation and granulating fluid (water and isopropanol) on the pseudopolymorphic transition of theophylline anhydrous (THA) in controlled release formulations as well as the implications of this transition on critical quality attributes of the tablets. Accordingly, 12 formulations were prepared using a full factorial screening design and monitored over a 3 month period at 40 °C and 75%. Physicochemical characterization revealed a drastic drop in tablet hardness accompanied by a very significant increase in moisture content and swelling of all formulations. Spectroscopic analysis (ssNMR, Raman, NIR and PXRD) indicated conversion of THA to theophylline monohydrate (TMO) in all formulations prepared by aqueous wet granulation in as early as two weeks. Although all freshly prepared formulations contained THA, the hydration–dehydration process induced during aqueous wet granulation hastened the pseudopolymorphic conversion of theophylline during storage through a cascade of events. On the other hand, no solid state transformation was observed in directly compressed formulations and formulations in which isopropanol was employed as a granulating fluid even after the twelve weeks study period. The transition of THA to TMO resulted in a decrease in dissolution while an increase in dissolution was observed in directly compressed and IPA granulated formulation. Consequently, the impact of pseudopolymorphic transition of theophylline on dissolution in controlled release formulations may be the net result of two opposing factors: swelling and softening of the tablets which tend to favor an increase in drug dissolution and hydration of theophylline which decreases the drug dissolution. [ABSTRACT FROM AUTHOR]

The objective of the study was to evaluate the stability of warfarin products during use by patients or caregivers. For evaluation, three commercial products manufactured by different processes were selected and placed at 30°C/75%RH to simulate in use condition. Samples were withdrawn up to 12 weeks and analyzed for the physicochemical changes. Scanning electron microscopy demonstrated increasing holes and craters in the tablets over the timeframe. Near-infrared chemical imaging and powder X-ray powder diffraction corroborated the change arising from conversion of crystalline to amorphous forms of the drug. Hardness and disintegration time of the tablets were found to increase progressively. With increasing time, moisture contents of the products were found to increase and consequent decrease in isopropyl alcohol content of the product. Dissolution of the tablets in media at pH 4.5 demonstrated discrimination between crystalline and amorphous drug products. Overall, percent drug dissolved in each product at 30 min was found to decrease with increasing exposure time. Dissolution of drug decreased from 54% to 38% and 82% to 54% for the two products while the third product maintained consistently high level of dissolution. These results suggest that the drug product quality attributes can change during use. [ABSTRACT FROM AUTHOR]

Warfarin sodium (WS) is a narrow therapeutic index drug and its product quality should be thoroughly understood and monitored in order to avoid clinical performance issues. This study was focused on understanding the effect of manufacturing and formulation variables on WS product critical quality attributes (CQAs). Eight formulations were developed with lactose monohydrate (LM) or lactose anhydrous (LA), and were either wet granulated or directly compressed. Formulations were granulated either with ethanol, isopropyl alcohol (IPA) and IPA–water mixture (50:50). Formulations were characterized for IPA, water content, hardness, disintegration time (DT), assay, dissolution and drug physical forms (scanning electron microscopy (SEM), near infrared chemical imaging (NIR-CI), X-ray powder diffraction (XRPD) and solid state nuclear magnetic resonance (ssNMR)), and performed accelerated stability studies at 40 °C/75% RH for three days. The DT and dissolution of directly compressed formulations were faster than wet granulated formulations. This was due to phase transformation of crystalline drug into its amorphous form as indicated by SEM, NIR-CI, XRPD and ssNMR data which itself act as a binder. Similarly, LM showed faster disintegration and dissolution than LA containing formulations. Stability results indicated an increase in hardness and DT, and a decrease in dissolution rate and extent. This was due to phase transformation of the drug and consolidation with particles' bonding. In conclusion, the CQAs of WS product were significantly affected by manufacturing and formulation variables. [ABSTRACT FROM AUTHOR]

The focus of present investigation was to explore X-ray powder diffraction ( XRPD) and solid-state nuclear magnetic resonance (ss NMR) techniques for amorphous and crystalline tacrolimus quantification in the sustained-release amorphous solid dispersion ( ASD), and to propose discriminating dissolution method that can detect crystalline drug. The ASD and crystalline physical mixture was mixed in various proportions to make sample matrices containing 0%-100% crystalline-amorphous tacrolimus. Partial-least-square regression and principle component regression were applied to the spectral data. Dissolution of the ASD in the US FDA recommended dissolution medium with and without surfactant was performed. R2 > 0.99 and slope was close to one for all the models. Root-mean-square of prediction, standard error of prediction, and bias were higher in ss NMR-based models when compared with XRPD data models. Dissolution of the ASD decreased with an increase in the crystalline tacrolimus in the formulations. Furthermore, detection of crystalline tacrolimus in the ASD was progressively masked with an increase in the surfactant level in the dissolution medium. XRPD and ss NMR can be used equally to quantitate the crystalline and amorphous fraction of tacrolimus in the ASD with good accuracy; however, ss NMR data collection time is excessively long, and minimum surfactant level in the dissolution medium maximizes detection of crystalline reversion in the formulation. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1777-1786, 2015 [ABSTRACT FROM AUTHOR]

Abstract: The focus of present investigation was to evaluate the tannic acid (TA) complexes of cholorpheniramine maleate (CPM) and characterize it by a variety of physicochemical, dissolution, and electronic tongue methods. The complexes were prepared in various molar ratios by solvent evaporation method. They were characterized by spectroscopic, thermal, powder X-ray, electronic tongue, solubility and dissolution methods. FTIR (infrared red) spectra showed complex formation between the TA and CPM. Complex formation has significantly lowered the drug solubility and sustained its release for more than 24h in phosphate buffer pH 6.8. On the contrary, the release was much faster in the presence of Avicel PH 113 in the same molar ratio complex. The complex formulation has suppressed the bitter taste of CPM as indicated by Euclidean distance in electronic tongue evaluation. NIR-CI (near infrared chemical imaging) showed lower skew value that indicated the homogenous distribution of formulation components. The chemometric models were also developed using the NIR data. The model based on second derivative data was better in predicting the TA and CPM loading as indicated by higher values of R, R 2 and lower values of root mean square error and standard errors. Furthermore, it has a better accuracy and less biased in comparison to other models. In conclusion, the CPM tannate has a sustained release behavior and excipients play a major role in modifying its release. Additionally, the complexes with varying molar ratio of tannate to CPM have differential taste masking abilities than that of the pure drug. [Copyright &y& Elsevier]

Abstract: The stability of metoprolol tartrate tablets packaged in original high density polyethylene containers and repackaged in USP Class A unit-dose blister packs was investigated. Studies were conducted at 25°C/60% relative humidity (RH) for 52 weeks and at 40°C/75% RH for 13 weeks. The potency, dissolution, water content, loss on drying and hardness of the drug products were analyzed. Results indicated no differences in the stability between the tablets in both packages stored under 25°C/60% RH. No difference in potency was found in both packages under either condition. However, a significant weight increase due to moisture uptake was observed for the repackaged tablets stored under 40°C/75% RH. The weight increase was accompanied by a decrease in tablet hardness (6.5–0kp) and a increase in dissolution rate (51–92%) in 5min. Near-infrared (NIR) chemical imaging also monitored moisture uptake of the tablet non-invasively through the package. The observed changes in product stability may adversely affect the products bioavailability profile, even though the potency of the active drug remained within USP specification range of 90–110%. Study results suggest product quality can be negatively impacted even when using USP Class A repackaging materials. [Copyright &y& Elsevier]

Purpose. The stability of a gabapentin 300-mg capsule product in the original bulk containers and repackaged in unit dose blister strips was studied. Methods. Both products were stored for one year under long-term storage conditions (25 °C and 60% relative humidity [RH]) and for three months under accelerated storage conditions (40 °C and 75% RH) and tested for weight change, potency, and dissolution using validated analytical method. Results. The capsules in the original containers showed no change in weight during the study period. However, the repackaged drug product stored under long-term storage conditions and under accelerated storage conditions showed significant weight increases (p < 0.001) during the study period. No significant differences in potency between the original and repackaged drug products were detected. Potency exceeded 97% for the products stored under the long-term storage conditions and exceeded 95% for the products stored under the accelerated storage conditions. At 13 weeks, samples from the original container and the blister strips stored under the accelerated storage conditions showed quantitative levels of the lactam degradation product; however, these levels were within acceptable limits. No other difference was observed between the original and the repackaged drug products, and both products remained stable throughout the study period. Conclusion. Gabapentin 300-mg capsules in the original containers and repackaged in blister strips were stable up to one year under long-term storage conditions and up to three months under accelerated storage conditions. [ABSTRACT FROM AUTHOR]

Abstract: A simple isocratic reversed-phase HPLC method was developed and validated for the analysis of dissolution samples of gabapentin tablets and capsules. Separation of gabapentin from its major degradation impurity, 3,3-pentamethylene-4-butyrolactam was achieved on a Phenomenex Luna Cyano column using a methanol–acetonitrile–20mM KH2PO4 (pH 2.2) (5:5:90, v/v/v) mobile phase. The compounds were eluted isocratically at a flow rate of 1.25mL/min. Both compounds were analyzed with UV detection at 210nm. The method was validated according to USP Category I requirements for gabapentin. The validation characteristics included accuracy, precision, linearity, range, specificity and limit of quantitation. Robustness testing was also conducted to evaluate the effect of minor changes to the chromatographic system and to establish appropriate system suitability parameters. Validation acceptance criteria were met in all cases. This method was used successfully for the quality assessment of five gabapentin drug products. [Copyright &y& Elsevier]

Rifaximin (RFX) exhibit polymorphism and commercial formulation contains the α form. The polymorphic transformation of the RFX in the drug product have significant effect on the clinical outcome. The focus of present work was to understand effect of formulation component and manufacturing method, and exposure to stability condition on polymorphic stability and dissolution of RFX tablets. The RFX tablets containing 2.5, 5 and 10% glyceryl palmitostearate (GPS) were manufactured by direct-compression and wet-granulation followed by compression. Ethanol was used as a granulating solvent. The tablets were packed in pharmacy vials and exposed to 40 °C/75% RH for four weeks. The tablets were characterized for polymorphic form by X-ray powder diffraction (XRPD) and Fourier infrared spectroscopy (FTIR), assay and dissolution. Before exposure to stability condition, dissolution ranged from 78.0 ± 2.3 to 81.9 ± 3.5%, and 72.7 ± 2.0 and 75.9 ± 5.8% in directly compressed and ethanol-granulated formulations, respectively. GPS amount of 10% caused a decrease in dissolution albeit insignificant (p > 0.05). The polymorphic forms of RFX were α and γ in directly compressed and ethanol-granulated formulations, respectively. There was a decrease in dissolution rate and extent after exposure to 40 °C/75% RH in directly compressed formulations. On the other hand, only dissolution rate was affected in ethanol-granulated formulations. The dissolution ranged from 52.8 ± 2.0 to 70.0 ± 3.0% in directly compressed formulations after four weeks exposure to 40 °C/75% RH exposure. A decrease in dissolution was linked to polymorphic transformation of the drug and GPS in the formulations after exposure to stability condition. XRPD and FTIR data indicated α to β transformation in directly compressed formulations while no polymorphic change was observed in ethanol-granulated formulations. In conclusion, this study clearly showed effect of formulation and manufacturing variables, and stability exposure on the polymorphic stability and dissolution of RFX, which may have clinical ramification. [ABSTRACT FROM AUTHOR]

The focus of the study was to understand the effects of formulation and process variables on the printlets quality manufactured by selective laser sintering (SLS) 3D printing. The Box-Behnken response surface methodology was used to evaluate effects of individual variables and combinations thereof. The formulation and process variables studied were printing chamber temperature (°C, X 1), laser scanning speed (mm/sec, X 2) and lactose monohydrate concentration (%, X 3). The responses studied were weight of printlets (mg, Y 1), hardness (N, Y 2), disintegration time (sec, Y 3) and dissolved drug fraction in 15 min (%, Y 4). The values of Y 1 , Y 2 , Y 3 and Y 4 varied from 170.2–257.0 mg, 5.5–32.0 N, 20–120 s and 64.4–97.5%, respectively. The studied factors showed statistically significant effects on the dependent variables (p < 0.04). The correlation coefficient between empirical and model predicted values for Y 1 , Y 2 , Y 3 and Y 4 were 0.999, 0.992, 0.998 and 0.983, respectively. The model was validated by an independent experiment and actual values of the responses were in close agreement with model predicted values. Fourier transformed infrared spectroscopy indicated no chemical interactions between the components of the formulation during printing process. X-ray powder diffractograms suggested a decrease in crystallinity of the drug and lactose in the printlets. Chemical images indicated uniform distribution of the drug. Scanning electron microscopy and X-ray micro-CT scanning showed a very porous microstructure of the printlets with a porosity of about 37.89%. In conclusion, the SLS method of manufacturing provides a feasible and flexible avenue for fabricating dosage forms with tailored characteristics. [ABSTRACT FROM AUTHOR]

The focus of this work was to explore feasibility of using blends of cellulose esters (CA 320S, CA 3980-10 or CAB 171-15) and enteric polymers (C-A-P, Eudragit® L100 or HPMCP HP-55) for delayed and enteric coating of tablets containing either diclofenac sodium (DFS, high dose) or prednisone (PDS, low dose) drug. The core tablets of DFS or PDS were coated with polymer blends to achieve approximate weight gain of 5% and 10%. The coated tablets were characterized for dissolution (0.1 N HCl and phosphate buffer pH 6.8) and surface morphology. The surface morphology of CA 398-10 or CAB 171-15 based polymer blends was rough and fibrous. Less than 0.5% drug was dissolved in 120 min from 5% w/w coated tablets in acid-phase dissolution testing. The dissolution in phosphate buffer pH 6.8 medium varied from 16.2 ± 0.2 to 98 ± 2.1%, and 30.1 ± 0.5% to 101.7 ± 3.4% in 120 min from DFS and PDS coated tablets, respectively. Dissolution was less in CA 320S based blends compared to CA 398-10 or CAB 171-15 blends in phosphate buffer medium. Furthermore, there were no significant differences observed in dissolution profiles of coated tablets of DFS or PDS. This can be explained by dose of the drugs. Additionally, dissolution was higher in tablets coated with enteric polymer alone compared with the blends. In conclusion, core tablets can be coated with cellulose ester and enteric polymers blend to impart both delayed and enteric release feature to the tablets containing hydrophilic or hydrophobic drug. [ABSTRACT FROM AUTHOR]