Rajashree Mashru

Risk based approach for design and optimization of stomach specific delivery of rifampicin.

The research envisaged focuses on risk management approach for better recognizing the risks, ways to mitigate them and propose a control strategy for the development of rifampicin gastroretentive tablets. Risk assessment using failure mode and effects analysis (FMEA) was done to depict the effects of specific failure modes related to respective formulation/process variable. A Box-Behnken design was used to investigate the effect of amount of sodium bicarbonate (X1), pore former HPMC (X2) and glyceryl behenate (X3) on percent drug release at 1st hour (Q1), 4th hour (Q4), 8th hour (Q8) and floating lag time (min). Main effects and interaction plots were generated to study effects of variables. Selection of the optimized formulation was done using desirability function and overlay contour plots. The optimized formulation exhibited Q1 of 20.9%, Q4 of 59.1%, Q8 of 94.8% and floating lag time of 4.0 min. Akaike information criteria and Model selection criteria revealed that the model was best described by Korsmeyer-Peppas power law. The residual plots demonstrated no existence of non-normality, skewness or outliers. The composite desirability for optimized formulation computed using equations and software were 0.84 and 0.86 respectively. FTIR, DSC and PXRD studies ruled out drug polymer interaction due to thermal treatment.

Design and in vitro evaluation of a novel bioadhesive vaginal drug delivery system for clindamycin phosphate

To develop more effective treatment for bacterial vaginosis, bioadhesive film formulations of clindamycin phosphate (CL) for vaginal delivery were studied. The bioadhesive films were prepared by solvent evaporation method. A 32 full factorial design was utilized for optimization of the effect of independent variables such as amount of hydroxypropyl cellulose (X1), amount of xanthan gum (X2) on mechanical properties, and % drug retained on vaginal mucosa. The films were evaluated for various aesthetic and physicodynamic properties. Batch F86 showed highest overall desirability of 0.99. Batch F86 was considered optimal composition for a novel bioadheive vaginal formulation, as they have good peelability, high % elongation at break, moderate tensile strength, and retained on vaginal mucosa up to 8 h. Also, films were non-cytotoxic as indicated by negligible decrease in cell viability. Our study may provide a potential vaginal delivery system of CL against bacterial vaginosis.

Palatable reconstitutable dry suspension of artemether for flexible pediatric dosing using cyclodextrin inclusion complexation

The present research was conducted to investigate the inclusion complexation of artemether (ARM) with beta-cyclodextrin (CD) with the aim of masking the bitterness along with improving the drug release and preparing a stable palatable formulation of ARM especially for pediatrics. A physical mixture and kneaded system were prepared to study the inclusion complexation. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and scanning electron microscopy (SEM) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on drug release. Reconstitutable dry suspension was evaluated for angle of repose, sedimentation characterization and pH. In vitro drug release studies for physical mixture and kneaded system were performed at pH, 1.2 and 6.8. Bitterness score was evaluated using gustatory sensation test. The FTIR, DSC and XRPD studies indicated inclusion complexation in physical mixture and kneaded system. In addition, physical mixture and kneaded system exhibited improved drug release at pH, 1.2 and 6.8. To formulate palatable reconstitutable dry suspension of ARM, the 1:20M physical mixture was selected based on bitterness score. Reconstitutable dry suspension prepared using physical mixture (DS4), showed complete bitter taste masking, good flowability and ease of redispersibility. Taste evaluation of reconstitutable dry suspension in human volunteers rated tasteless with a score of 0 to DS4 and 3 to DS5 (reconstitutable dry suspension prepared using pure ARM). This conclusively demonstrated a stable and palatable reconstitutable dry suspension of ARM using CD inclusion complexation for flexible pediatric dosing.

HPTLC-Densitometric and RP-HPLC Method Development and Validation for Determination of Salbutamol Sulphate, Bromhexine Hydrochloride andEtofylline in Tablet Dosage Forms

Different HPTLC-densitometric and RP-HPLC methods are developed for the simultaneous determination of salbutamol sulphate, bromhexine hydrochloride and etofylline in pharmaceutical tablets. HPTLC method was based on separation of all three drugs followed by densitometric measurements of their spots at 275 nm using CAMAG, TLC scanner III. The separation was carried out on Merck HPTLC aluminium plates of silica gel 60 F254, using acetone: methanol: formic acid (9:3:0.01) as mobile phase at room temperature (25 ± 2°C). The HPLC separation was carried out using a mobile phase consisting of 0.02 M ammonium acetate buffer: organic phase (where organic phase MeOH: ACN in ratio of 70:30) adjusted to pH 4.5 with gradient elution. The column used was Waters Spherisorb®C18 bonded with 5 μm (4.6 x 250 mm) with a flow rate of 1 mL min-1 and UV detection at 275 nm simultaneously. The mean recovery ofboth HPTLC and HPLC methods were found to be within 99.44 to 99.85 % w/w. Both HPTLCdensitometric and RP-HPLC methods were statistically validated and can be used for analysis of combined dose tablet formulation containing salbutamol sulphate, bromhexine hydrochloride and etofylline.

Influence of chitosan crosslinking on bitterness of mefloquine hydrochloride microparticles using central composite design

The present work examines the influence of various process and product parameters on mefloquine hydrochloride (MFL) entrapped in crosslinked chitosan microparticles for masking the bitterness. A central composite design (CCD) was employed to investigate the effect of three process and product variables, namely amount of MFL, chitosan and sodium hydroxide (crosslinking agent) on the incorporation efficiency, particle size, drug release at pH 6.8 and bitterness score. The microparticles were prepared by ionotropic gelation method, with a hardening time of 60 min. The optimum condition for process and product variables was evaluated using desirability function. The model is further cross validated for bias. The optimized microparticles were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the crosslinking of chitosan significantly affects incorporation efficiency, particle size, drug release and bitterness score. The bitterness score was decreased to zero compared to 3+ of pure MFL. It can be inferred that the proposed methodology can be used to prepare MFL microparticles for bitter taste masking.

Effect of chitosan crosslinking on bitterness of artemether using response surface methodology.

This work examines the influence of various process parameters on artemether entrapped in crosslinked chitosan microparticles for masking bitterness. A central composite design was used to optimize the experimental conditions for bitterness masking. Critical parameters such as the amounts of artemether, chitosan and crosslinking agent have been studied to evaluate how they affect responses such as incorporation efficiency, particle size and drug release at pH 6.8. The desirability function approach has been used to find the best compromise between the experimental results. The optimized microparticles were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the crosslinking of chitosan significantly affects incorporation efficiency, particle size and drug release at pH 6.8. The bitterness score of microparticles was decreased to 0, compared with 3+ for pure artemether. The proposed method completed masked the bitter taste of artemether.

Design and optimization of artemether microparticles for bitter taste masking

Design and optimization of artemether microparticles for bitter taste masking The objective of the present investigation was to reduce the bitterness of artemether (ARM). Microparticles were prepared by the coacervation method using Eudragit E 100 (EE) as polymer and sodium hydroxide solution as nonsolvent for the polymer. A 32 full factorial design was used for optimization wherein the amount of drug (A) and polymer (B) were selected as independent variables and the bitterness score, particle size and drug release at pH, 1.2 and 6.8 were selected as dependent variables. Optimization was carried out using the desirability function. The optimized microparticles batch was characterized by FTIR and DSC. Multiple linear regression analysis revealed that reduced bitterness of ARM can be obtained by controlling the drug release of microparticles at pH 6.8 and increasing the amount of EE. The increase in the amount of polymer leads to reduction in drug release from microparticles at pH > 5 due to its insolubility and thus reduces bitterness. However, the increase in the amount of polymer results in improved dissolution, suggesting improved availability of ARM in stomach. Optimized microparticles prepared using 0.04 g of ARM and 15 mL of 1% (m/V) solution of EE showed complete bitter taste masking with improved drug release at pH 1.2. Dizajniranje i optimizacija mikrokapsula artemetera za maskiranje gorkog okusa Cilja ovog rada je bio maskirati gorki okus artemetera (ARM) mikrokapsuliranjem. Mikročestice su pripravljene metodom koacervacije pomoću Eudragita E 100 (EE) kao polimerne komponente i natrijevog hidroksida u kojem se polimer ne otapa. 32 faktorijalni dizajn upotrebljen je za optimizaciju. Količine ljekovite tvari (A) i polimera (B) izabrane su kao nezavisne varijable, a intenzitet gorkog okusa, veličina čestica i oslobađanje ljekovite tvari pri pH 1,2 i 6,8 izabrane su kao zavisne varijable. Optimizirane mikročestice karakterizirane su pomoću FTIR i DSC. Multipla linearna regresijska analiza otkrila je da se smanjenje gorčine artemetera može postići kontroliranjem oslobađanja ljekovite tvari pri pH 6,8 i povećanjem količine EE. Povećanje količine polimera smanjuje oslobađanje ljekovite tvari pri pH > 5 pa se smanjuje i gorčina. Međutim, povećanje količine polimera povećava topljivost ljekovite tvari, a time potencijalno i njenu raspoložljivost u želucu. U optimiziranim mikročesticama pripravljenim pomoću 0,04 g ARM i 15 mL 1% m/V otopine EE potpuno se maskirao gorki okus, a oslobađanje ljekovite tvari pri pH 1,2 bilo je poboljšano.

Inhalable liposomal dry powder of gemcitabine-HCl: Formulation, in vitro characterization and in vivo studies.

Pulmonary drug delivery system facilitates local instillation of anticancer drugs to lungs which has proven to be pioneering approach for treatment of lung cancer. This approach led the groundwork for delivering liposomal formulation directly to lungs. Gemcitabine-HCl is currently considered as most effective drug for management of lung cancer. However, its application is limited owing to its metabolism by enzymes present in plasma resulting in reduced efficacy and higher toxicity. In present study, lyophilisation technique was used to convert liposomes into dry powder inhaler, which was formulated using emulsification solvent evaporation technique. The physicochemical properties including size, morphology, entrapment efficiency, loading efficiency etc. of formulated liposomes were evaluated. The prepared liposomal DPI (LDPI) formulations were then examined for solid state characteristics and aerosol performance using cascade impactor. From all the formulations prepared, the LDPI formulated using trehalose as cryoprotectant presented required properties along with desirable deposition pattern. Finally, the optimized formulation was selected for in vitro cell line studies; in vivo studies and stability study. This formulated inhalable particles offers a promising approach for the management of lung cancer through regional chemotherapy.

Spectroscopic Determination of Trace Amounts of Selenium(IV) in Multivitamin with Multimineral Formulations Using 3,3′‐Diaminobenzidine Hydrochloride

Abstract A simple, rapid, sensitive, and selective spectroscopic technique has been developed for the determination of Se(IV) from multivitamin with multimineral pharmaceutical formulations. The method is based on the formation of stable yellow‐colored piazselenol complex by reaction of Se(IV) with 3,3′‐diaminobenzidine hydrochloride, which is then extracted in toluene and detected spectroscopically at 434 nm. The different analytical parameters affecting the method such as dye concentration, pH for extraction, solvent for extraction, stability of colored complex, Se(IV):dye ratio, and so forth, have been optimized. The method was found to be linear over an analytical range of 1–7 μg mL−1 with correlation coefficient of 0.9994. Limit of detection, limit of quantitation, and Sandells sensitivity were found to be 0.1665 μg mL−1, 0.5549 μg mL−1, and 0.0339 μg cm−2, respectively. The method was validated and found to be suitable for estimation of Se(IV) species in tablets and capsules. Satisfactory recovery from the spiked samples of standard Se(IV) suggests no interference of any excipients. The influence of foreign ions at the normal formulation levels are readily tolerated, and interference from Fe(II) ion is circumvented by the addition of EDTA. The developed method was compared with atomic absorption spectroscopy by t‐test, and no significant difference was observed.

Liposomes encapsulating native and cyclodextrin enclosed paclitaxel: Enhanced loading efficiency and its pharmacokinetic evaluation

Combination strategy involving cyclodextrin (CD) complexation and liposomal system was investigated for Paclitaxel (PTX) to improve loading. Complexation was done using 2,6-di-O-methylbetacyclodextrin (DMβCD). Sterically stabilized double loaded PEGylated liposomes (DLPLs) containing PTX and PTX-DMβCD complex were prepared by thin film hydration. Physicochemical characterization of complex and prepared DLPLs was carried out. Cytotoxic potential, hemolytic potential and pharmacokinetics of DLPLs were tested in comparison to Taxol®. Aqueous solubility of PTX increased by almost 3 × 104 folds due to complexation with DMβCD as compared to pure drug solubility. Liposomal system was found to have 162.8 ± 4.1 nm size, zeta potential of -5.6 ± 0.14 mV and 2-fold increase in drug loading to 5.8 mol % for PTX due to double loading. DLPLs had low hemolytic potential and higher cytotoxicity on SKOV3 cells with improvement in IC50 value by 4.2 folds as compared to Taxol® at 48 h. The anti-angiogenic potential of DLPLs was confirmed by 1.33 folds lesser wound recovery in SKOV3 cells compared to Taxol®. In-vivo pharmacokinetic evaluation of DLPLs in rats substantiates improvement in circulation time, higher plasma concentration and decreased clearance rate compared to Taxol®. An efficacious system with improved loading and pharmacokinetics was formulated as potential alternative for currently marketed PTX formulation.