In this study we employed the use of the Meteor computational software program to perform predictions in silico on 17 hepatotoxic drugs for determining human-specific drug metabolites. Congruence of the in silico predictions from a qualitative standpoint of drug metabolite structures was established by comparison to human in vivo drug metabolic profiles characterized in publically available clinical studies. A total of 87 human-specific metabolites were identified from the 17 drugs. We found that Meteor's positive predictions included 4 out of the 9 reported major metabolites (detected in excreta at a level of >10% of the administered p.o. dose) and 10 out of the 15 major phase II metabolites giving a total of 14 correctly predicted drug metabolite structures out of 23 major metabolites. A significant level of unconfirmed positive predictions resulted and discussion on reasons for this is presented. An example is given whereby the in silico metabolism prediction succeeded to predict the putative toxic pathway of one of the drugs whilst conventional rodent liver microsomal assays failed to predict the pathway. Overall, we describe a reasonable simulation of human metabolic profiling using this in silico method with this data set of hepatotoxic drugs now withdrawn from the market. We provide an in-depth and objective discussion of this first of its kind validation test using clinical study data with interest in the prediction human-specific metabolism. Further research is discussed on what areas need to be investigated to improve upon the predictive data. The strong potential of this method to predict human-specific drug metabolites suggests the utility of this computational tool to help support not only the discovery development of therapeutics but also the safety assessment in identifying drug metabolites early to protect patients prior to initiating clinical studies.

Salbutamol and theophylline are available in conventional dosage forms, administered four times a day, leading to saw tooth kinetics and resulting in ineffective therapy. The combination of these two drugs in a single dosage form will enhance the patient compliance and prolong bronchodilation. Various polymers, such as hydroxy propyl methylcellulose K4M (HPMC- K4M), hydroxy propyl methylcellulose K100M (HPMC- K100M), xanthan gum, ethyl cellulose and hydroxy propyl methylcellulose phthalate (HPMC-P) were studied. HPMC-P and HPMC- K4M were found to be best in controlling the release. In-vitro dissolution studies were carried out for all the bi-layered tablets developed using USP dissolution apparatus type 2 (paddle). It was found that the tablet FB15-FW3 showed 50% release of salbutamol in first hour and the remaining was released for eight hours. However, theophylline was found to be released as per the USP specifications. The IR spectrum was taken for FB15-FW3 formulation and it revealed that there is no disturbance in the principal peaks of pure drugs salbutamol and theophylline. This further confirms the integrity of pure drugs and no incompatibility of them with excipients. Also, formulation of FB15-FW3 has shown required release pattern and complies with all the evaluated parameters and comparable to the marketed formulation.

The main objective of this study was to compare the behaviour of drug release among the famotidine polymorphs prepared by using various additives and solvents, by solvent evaporation method. The famotidine polyvinyl pyrrolidone polymorphs with different concentrations (0.5, 1 and 1.5%) were prepared by using solvent evaporation method. In these polymorphs of different concentrations 1% w/v polymorphs showed better release. Similarly, famotidine polymorphs of Tween 80 with different concentrations, polyethylene glycol 1% w/v and methanol was prepared. Famotidine polymorphs prepared the PVP (1% w/v) showed better drug release and solubility. DSC, FTIR, SEM and XRD studies were carried out. DSC studies revealed that PVP polymorphs were found to stable compared to other polymorphs. FTIR studies of the polymorphs prepared indicated that there was an interaction found in all polymorphs except PVP polymorphs indicating the absence of drug-additive interaction. SEM studies of PVP and methanol polymorphs revealed that they are tabular and prismatic and columnar respectively. These changes in morphology were due to variations in face dimensions and also properties of additives and solvent used in the preparation. XRD studies revealed that there is an increase in crystallinity in methanol polymorphs when compared to PVP polymorphs and pure drug. The mechanism of drug release was determined using zero order, first order and Hixon-Crowel equations. From the drug release kinetics these polymorphs followed first order and Hixon-Crowel release kinetics, exhibited fair linearity in their dissolution data. Further, in vivo studies were carried out for the evaluation of antiulcer activity. Based upon the drug release pattern and its kinetics only two of the prepared polymorphs of famotidine i.e. famotidine PVP polymorphs and famotidine methanol polymorphs were selected for animal studies. Antiulcer studies were carried out using pylorus ligation model and estimation of antioxidant parameters was also done. In these studies also polymorphs of PVP showed better antiulcer activity and also significant antioxidant activity when compared to famotidine (pure) and famotidine methanol polymorphs. Hence in the present investigation, amongst the various polymorphs of famotidine prepared, PVP polymorphs were found to possess good dissolution behaviour, stability and absence of drug additive interactions. Further, in vivo studies confirmed the better therapeutic action of these PVP polymorphs over the pure drug and famotidine methanol polymorphs.

Poor aqueous solubility and bioavailability of drugs are one of the important factors affecting the absorption of drugs and consequently their therapeutic effectiveness. Celecoxib is a widely used anti-inflammatory agent, with special use in rheumatoid arthritis. It belongs to biopharmaceutical classification system (BCS) class II drug with low solubility and high permeability. The present study was aimed to prepare and characterize the microcrystals of celecoxib, employing in situ micronization technique by rapid solvent change approach to enhance the solubility and dissolution rate and to optimize the solvent and anti-solvent ratio (v/v) using hydrophilic stabilizers such as guar gum, maltodextrin and PVP K30. The prepared formulations were evaluated for percentage crystal yield, mean particle size, drug content and in vitro dissolution studies. Amongst the formulations prepared (F1-F9), F6 formulation containing maltodextrin as stabilizing agent at 0.1% w/v concentration with 1:6 ratio of solvent to anti-solvent (v/v) respectively was considered as optimized formulation in which percentage drug release was found to be 89.33% within 60 minutes in comparison with that of the pure drug dissolution of 30.26% only within 60 minutes. Characterization studies like SEM, DSC and XRD indicate the solubility enhancement of celecoxib microcrystals due to decrease in particle size when compared to that of pure drug. FT-IR spectroscopy studies revealed that there is no chemical interaction between the drug and stabilizer and crystalline habit modification occurs in the microcrystals without any polymorphic changes.

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