Buchi N. Nalluri

Physicochemical characterization and dissolution properties of nimesulide-cyclodextrin binary systems

The objective of this work is physicochemical characterization of nimesulide-cyclodextrin binary systems both in solution and solid state and to improve the dissolution properties of nimesulide (N) via complexation with α-, β, and γ-cyclodextrins (CDs). Detection of inclusion complexation was done in solution by means of phase solubility analysis, mass spectrometry, and 1H nuclear magnetic resonance (1H-NMR) spectroscopic studies, and in solid state using differential scanning calorimetry (DSC), powder x-ray diffractometry (X-RD), scanning electron microscopy (SEM), and in vitro dissolution studies. Phase solubility, mass spectrometry and 1H-NMR studies in solution revealed 1∶1 M complexation of N with all CDs. A true inclusion of N with β-CD at 1∶2 M in solid state was confirmed by DSC, powder X-RD and SEM studies. Dissolution properties of N-CD binary systems were superior when compared to pure N.

Nimesulide and β-Cyclodextrin Inclusion Complexes: Physicochemical Characterization and Dissolution Rate Studies

Complex formation of nimesulide (N) and β-cyclodextrin (βCD) in aqueous solution and in solid state and the possibility of improving the solubility and dissolution rate of nimesulide via complexation with βCD were investigated. Phase solubility studies indicated the formation of a 1:1 complex in solution. The value of the apparent stability constant Kc was 158.98 M−1. Solid inclusion complexes of N and βCD were prepared by kneading and coevaporation methods. Differential scanning calorimetry (DSC) studies indicated the formation of solid inclusion complexes of N-βCD at a 1:2 molar ratio in both the methods. Solid complexes of N-βD (1:1 and 1:2 M) exhibited higher rates of dissolution and dissolution efficiency values than the corresponding physical mixtures and pure drug. Higher dissolution rates were observed with kneaded complexes than with those prepared by coevaporation. Increases of 25.6- and 38.7-fold in the dissolution rate were observed, respectively, with N-βCD 1:1 and 1:2 kneaded complexes.

Tablet formulation studies on nimesulide and meloxicam-cyclodextrin binary systems.

The objective of this work was to develop tablet formulations of nimesulide-β-cyclodextrin (NI-β-CD) and meloxicam-γ-cyclodextrin (ME-γ-CD) binary systems. In the case of nimesulide, 3 types of binary systems—physical mixtures, kneaded systems, and coevaporated systems—were studied. In the case of meloxicam, 2 types of binary systems—physical mixtures and kneaded systems—were investigated. Both drug-CD binary systems were prepared at 1∶1 and 1∶2 molar ratio (1∶1M and 1∶2M) and used in formulation studies. The tablet formulations containing drug-CD binary systems prepared by the wet granulation and direct compression methods showed superior dissolution properties when compared with the formulations of the corresponding pure drug formulations. Overall, the dissolution properties of tablet formulations prepared by the direct compression method were superior to those of tablets prepared by the wet granulation method. Selected tablet formulations showed good stability with regard to drug content, disintegration time, hardness, and in vitro dissolution properties over 6 months at 40°C±2°C and 75% relative humidity.

In Vitro Skin Permeation Enhancement of Sumatriptan by Microneedle Application

Different dimensions of commercially available microneedle devices, namely, Admin- Patch(®) microneedle arrays (MN) (0.6, 0.9, 1.2 and 1.5 mm lengths) and Dermaroller(®) microneedle rollers (DR) (0.5 and 1mm lengths) were evaluated for their relative efficiency in enhancement of transdermal permeation of Sumatriptan (SMT). Solubility assessment of SMT was carried out using propylene glycol (PG), polyethylene glycol (PEG) in combination with saline (S) at different ratios and the order of solubility was found to be 70:30 > 80:20 > 90:10 %v/v in both PG:S and PEG:S. In vitro skin permeation studies were performed using PG:S (70:30 %v/v) as donor vehicle. A significant increase in cumulative amount of SMT permeated, steady state flux, permeability coefficient and diffusion coefficient values were observed after microneedle treatment, and the values were in the order of 1.5mm MN >1.2mm MN >0.9mm MN >1mm DR >0.6mm MN >0.5mm DR > passive permeation. Lag times were significantly shorter after longer microneedle application (0.24h for 1.5mm MN). Arrays were found to be superior to rollers with similar microneedle lengths in enhancing SMT permeation and may be attributed to higher density of microneedles and force of application onto skin. The in vitro flux values revealed that 2.5cm(2) area patch is sufficient for effective therapy after treatment of skin with 1.5mm MN. It may be inferred that microneedle application significantly enhances the transdermal penetration of SMT and that it may be feasible to deliver clinically relevant therapeutic levels of SMT using microneedle assisted transdermal delivery systems.

Effect of Excipients on Oxcarbazepine Release from Modified Release Matrix Tablets

The present investigation was undertaken with an objective of formulating modified release (MR) matrix tablets of Oxcarbazepine (OXC) an anti-epileptic drug, based on cellulose ether polymers like Hydroxy Propyl Methyl Cellulose (HPMC K4M and LVCR 100) and Hydroxy Propyl Cellulose (HPC JF) as drug release retardants to overcome poor patient compliance and exposure to high doses associated with currently marketed immediate release (IR) dosage forms. The tablets were prepared by direct compression process and evaluated for various physico- chemical/mechanical parameters. Among three polymers used, HPMC LVCR 100 is selected as release retardant based on the viscosity and gel formation during dissolution. The effect of different fillers like Avicel PH 101, Avicel PH 105, Pre gelatinized starch (PGS), maize starch with spray dried lactose (FLOWLAC) and Di-calcium phosphate (DCP) on OXC release was also studied and the OXC percent release at the end of 12h is in the order of DCP>FLOWLAC>Avicel PH 101>Avicel PH 105>PGS. Based on the dissolution data obtained with different fillers and keeping in view of the results from the pre compression studies, and gel layer retaining with the matrix tablets, Avicel PH 105 was selected as carrier to carry out further formulation development. Since, OXC is poorly water soluble drug, solubilizing agents like surfactants, cyclodextrins and polyethylene glycols were included in the formulations and their effect on OXC release was studied in order to achieve therapeutic effective levels. Formulations containing 20% (w/w) of Hydroxy Propyl-β-Cyclodextrin gave superior OXC release of 85.50 ± 1.62% at the end of 12hours and fulfils the regulatory requirement. The dissolution data was also evaluated for drug release kinetics and mechanisms.

Development and Evaluation of Mouth Dissolving Films of Amlodipine Besylate for Enhanced Therapeutic Efficacy

The present investigation was undertaken with an objective of formulating mouth dissolving films (MDFs) of Amlodipine Besylate (AMLO) to enhance convenience and compliance of the elderly and pediatric patients for better therapeutic efficacy. Film formers like hydroxy propyl methyl cellulose (HPMC) and methyl cellulose (MC) along with film modifiers like poly vinyl pyrrolidone K30 (PVP K30), and sodium lauryl sulphate (SLS) as solubilizing agents were evaluated. The prepared MDFs were evaluated for in vitro dissolution characteristics, in vitro disintegration time, and their physicomechanical properties. All the prepared MDFs showed good mechanical properties like tensile strength, folding endurance, and % elongation. MDFs were evaluated by means of FTIR, SEM, and X-RD studies. MDFs with 7.5% (w/w) of HPMC E3 gave better dissolution properties when compared to HPMC E5, HPMC E15, and MC. MDFs with PVP K30 and SLS gave superior dissolution properties when compared to MDFs without PVP K30 and SLS. The dissolution properties of MDFs with PVP K30 were superior when compared to MDFs with SLS. In the case of F3 containing 7.5% of HPMC E3 and 0.04% of PVP K30, complete and faster release was observed within 60 sec when compared to other formulations. Release kinetics data reveals diffusion is the release mechanism.

Stability-indicating Method for the Estimation of Riluzole in Tablets.

A stability-indicating reverse-phase high-pressure liquid chromatography method with photodiode array detector was developed and validated for estimation of riluzole in the bulk and tablet dosage forms. Riluzole was subjected to stress conditions (light, heat, humidity, acid/base hydrolysis and oxidation) and the stressed samples were analyzed by developed method. Degradation was observed in acidic, basic, oxidative and thermal conditions. The degradation products were well resolved from riluzole peak. An inertsil-ods column (250×4.6 mm, 5 μ) with a mobile phase comprising 0.02% v/v formic acid:acetonitrile(35:65 v/v) at a flow rate of 1.0 ml/min was used and eluents were monitored at 260 nm. The retention time of riluzole was 5.7 min. Complete validation for the method was carried out according to Internation Conference on Harmonization guidelines. Linearity was achieved in the range 10-50 μg/ml with a correlation coefficient (r) 0.9998. The percent assay was 100.92 and mean percentage recovery was found to be 101.10.

Microneedle-assisted transdermal delivery of Zolmitriptan: effect of microneedle geometry, in vitro permeation experiments, scaling analyses and numerical simulations

Abstract Objective: The present study was aimed to investigate the effect of salient microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation enhancement of Zolmitriptan (ZMT). Methods: Two types of MN devices viz. AdminPatch® arrays (ADM) (0.6, 0.9, 1.2 and 1.5 mm lengths) and laboratory fabricated polymeric MNs (PM) of 0.6 mm length were employed. In the case of PMs, arrays were applied thrice at different places within a 1.77 cm2 skin area (PM-3) to maintain the MN density closer to 0.6 mm ADM. Scaling analyses was done using dimensionless parameters like concentration of ZMT (Ct/Cs), thickness (h/L) and surface area of the skin (Sa/L2). Results: Micro-injection molding technique was employed to fabricate PM. Histological studies revealed that the PM, owing to their geometry/design, formed wider and deeper microconduits when compared to ADM of similar length. Approximately 3.17- and 3.65-fold increase in ZMT flux values were observed with 1.5 mm ADM and PM-3 applications when compared to the passive studies. Good correlations were observed between different dimensionless parameters with scaling analyses. Numerical simulations, using MATLAB and COMSOL software, based on experimental data and histological images provided information regarding the ZMT skin distribution after MN application. Discussion: Both from experimental studies and simulations, it was inferred that PM were more effective in enhancing the transdermal delivery of ZMT when compared to ADM. Conclusions: The study suggests that MN application enhances the ZMT transdermal permeation and the geometrical parameters of MNs play an important role in the degree of such enhancement.

RAPID ANALYSIS OF FINASTERIDE IN BULK AND FORMULATIONS BY RP-HPLC-PDA METHOD

A simple, precise, rapid and accurate LC-MS compatible RP-HPLC-PDA method has been developed and validated for the estimation of Finasteride (FIN) in bulk and tablet formulations. The chromatographic separation was achieved on Phenomenex C 18 column (150 mm x 4.6 mm, 5.0 μ particle size) using the mobile phase comprising 0.02% formic acid (in water): methanol in the ratio of 20:80 (v/v) at a flow rate of 1mL/min and FIN was eluted at 3.4 min. Quantification and linearity were achieved at 220 nm over the concentration range of 5-50 μg/mL and the percentage mean of assay was found to be 100.29. The method was validated for specificity, linearity, accuracy, precision, LOD, LOQ, stability and robustness as per the ICH guidelines and is suitable to be employed in Quality Control.

Development of Validated Stability Indicating RP-HPLC-PDA Method for Camptothecin Analysis -

A novel stability-indicating RP-HPLC-PDA method was developed and validated for quantitative determination of Camptothecin (CPT) in bulk, formulation and in dissolution samples using Inertsil-C18 (250mm x 4.6mm, 5μm) column with mobile phase combination of 15mM Ammonium acetate and acetonitrile (60:40) at a flow rate of 1mL/min. Eluents were monitored at a wavelength of 254 nm with an injection volume of 20�L. CPT was completely degraded in oxidative and base hydrolysis conditions and around 37% in acidic conditions and no degradation of CPT was observed with thermal, thermal/humidity and photo conditions. CPT showed linearity over a concentration range of 2-10μg/mL with a regression coefficient (R2) of 0.994 and correlation coefficient (R) of 0.999. The limit of detection (LOD) and limit of quantification (LOQ) values for CPT were 0.025μg/mL and 0.077μg/mL respectively. The developed method was validated as per ICH guidelines. The method was also successfully applied to dissolution testing of controlled release formulation.