FORMULATION OPTIMIZATION AND CHARACTERIZATION OF AQUEOUS INJECTION CONTAINING POORLY SOLUBLE DRUG USING MIXED HYDROTROPIC SOLUBILIZATION

Objective: Mefenamic acid (MFA) is an NSAID that exhibits anti-inflammatory analgesic and antipyretic activity. Peak plasma levels are attained in 2-4 h and the elimination half-life approximates 2 h, repetitive administration of tablets for 3-5 times a day is desired. It is supplied only in the form of tablets for oral administration. In acute conditions drug administered parenterally could give rapid relief from severe symptoms like pain. Thus, formulation of injectable formulation of MFA could be better alternative compared to conventional tablet dosage form. The low aqueous solubility of MFA precludes its use in parenteral formulation development. Methods: In this work attempt were made to enhance the aqueous solubility of mefenamic acid using mixed solvency technique. For that different hydrotropic agents such as Urea, Sodium acetate, sodium benzoate, sodium citrate and their blends were evaluated. Optimal concentration of hydrotropic agent in blend was determined using D-optimal mixture experimental design. The optimized bled was used to develop the aqueous injection of mefenamic acid. The developed injection was subjected for various quality control tests and stability of developed formulation was also evaluated. Results: The aqueous solubility in optimized blend of hydrotropic agent batches (U: SA: SB: SC, 4:4:23:9 %w/v) showed 835.71-fold compared to MFA solubility in distilled water. The quality control tests for parenteral formulation and accelerated stability study were found to be within prescribed limits and stable. Conclusion: The inadequate solubility of MFA was overcome, and aqueous injection was successfully developed which can be serve as cost effective treatment in various indications.

Using Volumetric Method the Study of Molecular Interactions of NSAID (DP) in Water and Water + 1M Urea at Different Temperatures

Understanding possible interactions of drugs and the factors that command such interactions could be helpful to control their disadvantageous effects upon human health. In this study, volumetric properties for the solution of diclofenac potassium (DP), a non-steroidal anti-inflammatory drug (NSAID), were investigated for the first time to look into its molecular interactions at four different temperatures varying from 298.15 K to 313.15 K at 5 K intervals in water as well as aqueous hydrotropic agent urea (1M) solutions. Experimental density data obtained using a pycnometer have been taken to estimate apparent molar properties, i.e., limiting apparent molar volume (〖V_ɸ〗^0), apparent molar volume (V_ɸ), limiting apparent molar expansibility (〖E_ɸ〗^0) and apparent molar expansibility (E_ɸ). The results obtained were discussed in terms of solute-solvent and solute-solute interactions in the studied systems. The obtained results from volumetric data were explored in terms of the existence of solute-solvent interactions in aqueous systems of drug solutions.

Improving solubility and dissolution of meloxicam by solid dispersion using hydroxypropyl methylcellulose 2910 3 cps and nicotinamide

Background Solid dispersion (SD) represents a good method for enhancing the solubility of poorly water-soluble drugs. Meloxicam (MLX), a nonsteroidal anti-inflammatory drug has poor solubility in water. Hydroxypropyl methylcellulose (HPMC) 2910 3 cps, a hydrophilic carrier and nicotinamide (NC), a hydrotropic agent can be used as matrix of SD. The aim of this study is to investigate the effect of HPMC 2910 3 cps and NC as SD matrix on the solubility and dissolution rate of MLX. Methods The SD of MLX was prepared by solvent evaporation method using methanol as solvent. The SD formulations composed of HPMC and NC in different ratios (1:1:1, 1:1:2, 1:2:1, 1:2:2). The physical state of MLX SD were characterized by Differential Thermal Analyzer (DTA), Fourier Transform Infrared Spectroscopy, powder X-ray diffractometer (PXRD), Scanning Electron Microscopy (SEM). The solubility and dissolution of the MLX SD were also evaluated. Results The results of differential thermal analysis (DTA) showed that the melting point of MLX SD was lower than MLX further the X-ray diffractogram showed a decrease of the crystallinity of MLX in SD. Those indicated that MLX was dispersed molecularly in SD. The SD showed a widening transmission peak at 3000–3500 cm−1 which resembled the peak of pure MLX transmission. It indicated that intermolecular hydrogen bonds were formed between MLX, HPMC, and NC. The solubility and the dissolution efficiency (ED60) of SD with MLX-HPMC 2910 3 cps-NC = 1:2:1 increased 3.59 times and 1.50 times higher then MLX substance. Conclusions MLX-HPMC-NC SD system increased the solubility and dissolution of MLX. The SD with MLX-HPMC 2910 3 cps-NC ratio of 1:2:1 had the highest solubility and ED60 compared to the other SD formulas.

Mathematical Modelling and Simulation of Hydrotropic Delignification

A B S T R A C TDelignification is a fundamental step in bio-refinery for lignocellulose feedstock processing. Hydrotropic delignification is considered as a promising alternative compared to other conventional delignification processes due to the use of mild chemicals. In this paper, a quantitative description of hydrotropic delignification for a cylindrical biomass particle is presented by using fundamental concepts of chemical kinetics and transport processes. The development of hydrotropic delignification model was based on following assumptions: i) lignin in the biomass is immobile, ii) delignification is considered as a simultaneous process which involves intra-particle diffusion of hydrotropic agent followed by second order reaction for lignin and hydrotropic chemical, as well as intra-particle product diffusion. Finite difference approximation was applied to solve the resulting partial and ordinary differential equations. The simulation results of the proposed model may describe the concentration profiles of lignin, hydrotropic agent and soluble product distributions in a cylindrical solid particle as a function of radial position and time. In addition, the model could also predict the concentration of hydrotropic agent and soluble product in the liquid phase as well as the yield and conversion as a function of time. A local sensitivity analysis method using one factor at a time (OFAT), has been applied to investigate the influence of particle size and hydrotropic agent concentration to the yield and conversion of the hydrotropic delignification model. Validation of the proposed model was conducted by comparing the numerical results with an analytical solution for a simple case diffusion in cylinder with constant surface concentration and in the absence of chemical reaction. The validation result showed that the hydrotropic delignification model was in good agreement with the analytical solution.Keywords: cylindrical particle; delignification; hydrotropic; modelling; simulation A B S T R A KDelignifikasi merupakan tahap penting dalam proses biorefineri biomassa berlignoselulosa. Delignifikasi hidrotropi adalah salah satu alternative proses yang memiliki beberapa kelebihan dibandingkan proses-proses delignifikasi konvensional karena tidak menggunakan bahan kimia berbahaya. Dalam artikel ini disajikan deskripsi kuantitatif proses delignifikasi hidrotropi untuk partikel berbentuk silinder dengan menggunakan konsep fundamental kinetika reaksi dan proses-proses perpindahan. Penyusunan model proses delignifikasi hidrotropi dilakukan berdasarkan asumsi-asumsi bahwa i) lignin pada biomassa bersifat immobile, ii) proses delignifikasi dipandang sebagai suatu rangkaian proses simultan yang terdiri atas proses difusi intrapartikel senyawa hidrotrop, reaksi order dua terhadap lignin dan senyawa hidrotrop, serta difusi intrapartikel produk delignifikasi. Finite difference approximation (FDA) digunakan untuk menyelesaikan persamaan simultan berbentuk persamaan diferensial ordiner dan persamaan diferensial parsial dalam tahap pemodelan. Hasil simulasi memberikan gambaran profil distribusi konsentrasi lignin, konsentrasi senyawa hidrotrop dan produk delignifikasi di dalam partikel padatan yang berbentuk silinder sebagai fungsi posisi dan waktu. Model yang dikembangkan juga dapat memprediksi konsentrasi senyawa hidrotropik dan produk di fasa cairan, serta yield dan konversi sebagai fungsi waktu. Metode analisis sensitivitas lokal, yakni metode one factor at a time (OFAT), digunakan untuk mengkaji pengaruh ukuran partikel dan konsentrasi senyawa hidrotropik terhadap yield dan konversi proses delignifikasi. Validasi model yang diajukan dilakukan dengan membandingkan hasil analisa numerik dengan hasil penyelesaian analitis untuk kasus difusi pada silinder dengan konsentrasi permukaan yang konstan serta tidak melibatkan reaksi kimia. Hasil validasi model menunjukkan bahwa model delignifikasi hidrotropi yang diajukan memiliki kesesuaian yang tinggi dengan hasil penyelesaian analitis.Kata kunci: delignifikasi; hidrotropi; pemodelan; silinder; simulasi

HYDROTROPIC SOLUBILISATION OF IRBESARTAN: MECHANISTIC STUDY AND DISSOLUTION PROFILING

Irbesartan (IB) is a water insoluble drug belonging to BCS II that exerts its anti-hypertensive effect through the blockage of angiotensin II receptors. The aqueous insolubility of IB limits its bioavailability and overall efficacy. Hydrotrophy, a solubilization technique to achieve an augmentation in aqueous solubility of poorly water-soluble drugs, has recently gained a lot of interest due to its safety, economics, and use of non-toxic and non-flammable adjuvants. The present study deals with application of hydrotrophy techniques to increase the solubility of IB using sodium benzoate and urea as the hydrotropic agent. The results showed a significant enhancement in dissolution profile of IB as compared to non-hydrotropic drug. The dissolution rate and solubility comparison of both hydrotropic agents revealed that sodium benzoate has a better solubilizing efficiency than urea. Hence, it can be concluded that hydrotropic concept can be adopted as a solubility enhancement technique for poorly water-soluble drugs.

UV-Spectrophotometric Determination of Nateglinide in Bulk and Pharmaceutical Dosage Form Using Hydrotropic Solubilization Technique

Nateglinide is practically insoluble in water, sparingly soluble in strong acid; soluble in strong bases. It is an anti-diabetic, effective in treatment of diabetes. Solubility of Nateglinide is increased by using 0.1M Piperazine as a hydrotropic agent. Nateglinide showed the maximum absorbance at 220nm. At this wave length, hydrotropic agent and other tablet excipients did not show any significant interference in the spectrophotometric assay. The developed methods were found to be linear in the range of 5-30µg/ml with correlation coefficient r2 of 0.9966. The mean percent label claim of tablets of Nateglinide in formulation estimated by the proposed method was found to be 98.05%, 98.07%, 99.15%. The developed methods were validated according to ICH guidelines and values of accuracy, precision and other statistical parameters were found to be in good accordance with the prescribed values. As hydrotropic agent was used in the proposed methods, these methods were eco-friendly and it can be used in routine quantitative analysis of drug in bulk and dosage form in industries.