Coating characterization by hyperspectroscopy and predictive dissolution models of tablets coated with blends of cellulose acetate and cellulose acetate phthalate.

The objective of current research was to develop the models of dissolution prediction of tablets coated with cellulose acetate (CA 320S or CA 398-10) and cellulose acetate phthalate (C-A-P) blends. Independent variables selected were coating percent (X1) and percent of CA 320S or CA 398-10 (X2) in the blend. Dependent variables selected were dissolution in 1 (Y1), 8 (Y2), and 24 h (Y3). Diclofenac sodium core tablets were coated with blend of either CA 320S and C-A-P or CA 398-10 and C-A-P at approximately 5, 7.5, and 10% weight gain. CA 320S and CA 398-10 content in the corresponding blends varied from 33.3-66.7% and 25.0-50.0% relative to C-A-P, respectively. Dissolution was performed in phosphate buffer 6.8 using USP apparatus 2. Coated tablets were also characterized for surface morphology and coating uniformity by near infrared hyperspectroscopy. Y1, Y2, and Y3 were statistically (p < 0.05) affected by X2 in CA 320S/C-A-P and CA 398-10/C-A-P blends coated tablets. On the other hand, X1 had statistically significant (p < 0.05) effect only on the Y3 in CA 320S/C-A-P while Y1 was statistically (p < 0.05) affected by X2 in CA 398-10/C-A-P. Analysis of variance also indicated statistically significant (p < 0.05) effect of the studied variables on the dependent variables for both the blends. The models were verified by independent experiment. Model predicted and empirical values of Y1, Y2, and Y3 were close with maximum residual of 7.0%. In conclusion, dissolution can be modulated by varying composition of blend, polymer type, and coating weight.

Salt Engineering of Aripiprazole with Polycarboxylic Acids to Improve Physicochemical Properties.

Aripiprazole (APZ) has poor physicochemical properties and bitter taste. The current study aimed to prepare salts of APZ with polycarboxylic acids (citric, malic, and tartaric acids) to improve physicochemical properties and impart sour taste to the drug. The salts were prepared by solubilization-crystallization method, and characterized by electron microscopic, spectroscopic, diffractometry, and thermal methods. The salts were assessed for pH solubility, pH-stability, dissolution, and solid-state stability. Fourier transformed infrared, X-ray powder diffraction, and differential scanning calorimetry data indicated formation of new solid phases. APZ and the salts exhibited pH-dependent solubility. The pH solubility curve shape was inverted "V," inverted "W," and inverted "U" for APZ, APZ-Citrate, and APZ-Malate and APZ-Tartrate, respectively. Compared to APZ, the solubility of salts at pH 4, 5, and 6 was 3.6-7.1, 23.9-31.5, and 143.4-373.3 folds of APZ. Increase in solubility in water by citrate, malate, and tartrate salts was 5562.8, 21,284.7, and 22,846.7 folds of APZ. The salt formation also leads to an increase in rate and extent of dissolution. The dissolution extent was 3.5 ± 0.5, 71.3 ± 1.2, 80.1 ± 6.2, and 86.1 ± 1.1% for APZ, APZ-Citrate, APZ-Malate, and APZ-Tartrate, respectively. Liquid and solid-state stabilities of the salts were comparable to APZ. In conclusion, salts of APZ with polycarboxylic acids improved solubility, and dissolution, and impart sour taste, which may improve palatability of the drug.

Development of a Multivariate Predictive Dissolution Model for Tablets Coated with Cellulose Ester Blends.

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.

Studying effect of glyceryl palmitostearate amount, manufacturing method and stability on polymorphic transformation and dissolution of rifaximin tablets.

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 ß 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.

Development of Abuse-Deterrent Formulations Using Sucrose Acetate Isobutyrate.

The objective of the present investigation was to understand the effect of sucrose acetate isobutyrate (SAIB) on abuse-deterrent properties (ADPs) of abuse-deterrent formulations (ADFs) based on Polyox™. SAIB would enhance ADPs of Polyox™-based formulations due to its glassy liquid and hydrophobic properties. Formulations were prepared by granulation followed by compression and heat curing at 90°C. The formulations were evaluated for surface morphology, hardness, manipulation in coffee grinder, particle size distribution, drug (pseudoephedrine hydrochloride) extraction in water, alcohol, 0.1 N HCl, 0.1 N NaOH at room temperature and elevated temperature using microwave and oven, syringeability and injectability, and dissolution. The heat curing of formulations significantly increased the hardness (> 490 N). Addition of SAIB imparted elasticity to formulations and decreased brittleness as indicated by lower values of work done and gradient compared to control formulations. After grinding, about 7.7-25.6% of the powder remained on the sieve (1 mm pore opening), D90 was 53.1-136.7 µm more, and Q (fraction < 500 µm) was 17.8-40.7% less in SAIB-based formulations compared to control formulations. Drug extraction between control and test intact formulations was similar. However, drug extraction was 23.9-42.5% (water), 20.6-26.1% (0.1 N HCl), and 37.4-50.6% (0.1 N NaOH) less in SAIB-based powder cured and uncured formulations compared to control formulations. Dissolution varied from 65.6 ± 4.2 to 97.6 ± 4.0% in 9 h from the formulations. In conclusion, addition of SAIB to Polyox™-based ADFs has synergistic effect on ADPs. This would further decrease potential of drug abuse/misuse by various routes.

Development of Methamphetamine Abuse-Deterrent Formulations Using Sucrose Acetate Isobutyrate.

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.

Application of salt engineering to reduce/mask bitter taste of clindamycin.

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.

Univariate and Multivariate Models for Determination of Prasugrel Base in the Formulation of Prasugrel Hydrochloride Using XRPD Method.

Prasugrel hydrochloride (PHCl) undergoes salt disproportionation, and the resulting prasugrel free base (PFB) may lead to the poor in vitro and or in vivo performance of the drug product. The aim of the present work was to develop univariate and multivariate models based on X-ray powder diffraction to quantify the salt and base in the powder and tablet formulations. Compositionally identical formulations of PHCl and PFB were prepared and mixed in various proportions to make 0%-30% PFB sample matrices. The formulations consisted of commonly used excipients, which are generally used in commercially available products. X-ray powder diffraction data were collected and subjected to the least square regression and partial least square regression analysis. The model performance parameters such as root mean squared and standard errors were low for univariate models compared to partial least square regression multivariate models. Model predicted values of the independent sample matrices by both methods matched closely with the actual values of PFB and PHCl. However, residual and standard deviation were low in univariate models predicted values. The models developed in this work have been shown to quantitate the PHCl disproportionation to PFB fraction in the drug product and provide a means to control the disproportionation of PHCl.

Blend of cellulose ester and enteric polymers for delayed and enteric coating of core tablets of hydrophilic and hydrophobic drugs.

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 ±â€¯0.2 to 98 ±â€¯2.1%, and 30.1 ±â€¯0.5% to 101.7 ±â€¯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.

Chemometric Models for Quantification of Carbamazepine Anhydrous and Dihydrate Forms in the Formulation.

Carbamazepine (CBZ) exists in anhydrous and dihydrate forms. These forms differ in their solubility, dissolution rate, and subsequently in their oral bioavailability. The objective of this study is to develop multivariate chemometric models for estimation of the low level of carbamazepine dihydrate (CBZ-DH) in the CBZ formulations containing excipients of the commercial formulation. The selected excipients were mixed in proportions to make sample matrices ranging from 0% to 50% CBZ-DH. Fourier transform infrared (FTIR), near infrared (NIR), and hyperspectral imaging data were mathematically pretreated before the development of partial least square and principal component analysis regression models. The developed partial least squares regression and principal component analysis models demonstrated predictability of CBZ and CBZ-DH by multiple scattering correction and standard normal variate processing methods. Among the spectroscopic techniques used the model performance parameters such as root-mean-square error, standard error, and bias were found to be low for NIR compared to FTIR. The treated data have shown better model fitting than without treatment, which was demonstrated by correlation coefficient of 0.9778, 0.9824, and 0.9852 for FTIR, NIR, and hyperspectral imaging, respectively. Furthermore, the predicted values were found to be very close to the selected low level of independent samples having 5% CBZ-DH in tablet formulation.

Development and Validation of a Discriminatory Dissolution Method for Rifaximin Products.

The commercial product of rifaximin (RFX) contains α form. The α form can change to ß 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 ß form. The objective of this study was to develop a discriminatory dissolution method that can detect low levels of α to ß transformation in RFX products. Formulations containing a variable fraction of α and ß 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 ß forms. The developed method can detect polymorphic transformation if there is 25% or more ß form conversion.

Quality and In-Use Stability Comparison of Brand and Generics of Extended-Release Phenytoin Sodium Capsules.

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.

Effect of processing parameters and controlled environment storage on the disproportionation and dissolution of extended-release capsule of phenytoin sodium.

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 ±â€¯3.83% to 42.34 ±â€¯4.31%, and 63.96 ±â€¯6.12 to 46.53 ±â€¯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.

Quantitative estimation of phenytoin sodium disproportionation in the formulations using vibration spectroscopies and multivariate methodologies.

Phenytoin sodium (PS) has a tendency to convert to its base form; phenytoin base (PHT) during manufacturing, packaging, shelf life and in-use conditions that can influence its clinical performance. The objective of the present work was to develop a non-destructive, quick and easy analytical method for quantification of PHT in the drug product. A formulation was prepared to contain the excipients of commercial capsule formulation of PS. The formulation containing either 100% PHT or PS was prepared and these formulations were mixed in different proportion to achieve 0-100% PHT matrices. FTIR, NIR and Raman spectra of samples were collected. Data were truncated and mathematically pretreated before development of partial least squares (PLS) and principal component analysis (PCA) regressions model. The models were assessed by slope, intercept, R, R2, root mean square error (RMSE) and standard error (SEP). The models exhibited good linearity over the selected range of PHT in the formulations with low error as indicated by slope that was close to one and small values of intercept, RMSE and SE. The models of NIR based data were more accurate and precise than Raman data based models as indicated by the low values of RMSE and SE. Prediction accuracy of independent samples containing 25% PHT using NIR models were similar to Raman models. On the other hand, the prediction was more precise for the independent sample containing 5% PHT using NIR data based models compared to Raman data based models as indicated by standard deviation. In conclusion, chemometric models based on NIR and Raman spectroscopies provides a fast and easy way to monitor the disproportionation of PS in the drug products.