Rutesh H. Dave

To evaluate the change in release from solid dispersion using sodium lauryl sulfate and model drug sulfathiazole

The solubility of drugs remains one of the most challenging aspects of formulation development. There are numerous ways to improve the solubility of drugs amongst which the most promising strategy is solid dispersion. Different ratios of sulfathiazole: PVP-K29/32: sodium lauryl sulfate (SLS) were prepared (1:1:0.1, 1:1:0.5, 1:1:1) and various methods were employed to characterize the prepared solid dispersions, namely modulated differential scanning calorimeter, X-ray powder diffraction, Fourier Transformed Infrared Spectroscopy and dissolution studies. Lack of crystallinity was observed in internal and external systems suggesting a loss of crystallinity, whereas the physical mixtures showed a characteristic peak of sulfathiazole. In vitro dissolution results clearly showed that the incorporation of a relatively small amount of surfactants (5, 20 or 33% w/w) into a solid dispersion can improve its dissolution rates compared to binary solid dispersion (SD) alone and pure sulfathiazole. In all ratios solid dispersion internal shows a higher dissolution rate compared to a physical mixture and solid dispersion external which suggests that the way that the surfactant is incorporated into the solid dispersion plays an important role in changing the solubility of a drug. The solubilization mechanism is mainly responsible for this higher dissolution rate when we incorporate the SLS in SD.

Impact of Nanosizing on Solubility and Dissolution Rate of Poorly Soluble Pharmaceuticals

The quantitative determination of solubility and the initial dissolution rate enhancement of crystalline nanoparticles were critically investigated using a separation-based approach (ultracentrifugation and filtration). Four poorly soluble model compounds (griseofulvin, celecoxib, compound-X, and fenofibrate) were used in this investigation. The effect of the stabilizer concentration on the solubility of the unmilled compound was determined first to quantify its impact on the solubility and used for comparing solubility enhancement upon nanosizing. Methodologies were established for ultracentrifugation, ensuring satisfactory separation of crystalline nanoparticles. The data obtained using separation-based methodologies proved to be accurate, reproducible, and were in fair agreement with what would be predicted from the Ostwald-Freundlich equation. The dissolution studies under sink conditions were proved to be less efficient in quantifying the initial dissolution rate of crystalline nanoparticles. Nonsink dissolution experiments were able to reduce the high-dissolution velocity of nanoparticles and generated the best discriminative dissolution profile. The enhancement in initial dissolution rate was significantly less than that expected from the Noyes-Whitney equation based on surface area change. This discriminatory dissolution method can potentially be used further in the modeling of crystalline nanoparticles during drug development.

Investigation of the effects of process variables on derived properties of spray dried solid-dispersions using polymer based response surface model and ensemble artificial neural network models

The objective of this study was to use different statistical tools to understand and optimize the spray drying process to prepare solid dispersions. In this study we investigated the relationship between input variables (inlet temperature, feed concentration, flow rate, solvent and atomization parameters) and quality attributes (yield, outlet temperature and mean particle size) of spray dried solid dispersions (SSDs) using response surface model and ensemble artificial neural network. The Box Behnken design was developed to investigate the effect of various input variables on quality attributes of final products. Moreover, Pearson correlation analysis, self organizing map, contour plots and response surface plot were used to illustrate the relationship between input variables and quality attributes. The influence of different physicochemical properties of solvent on the quality attributes of spray dried products was also investigated. Final validation of prepared models was done using binary SSDs of six model drugs with PVP. Results demonstrated the effectiveness of proposed PVP based model which can help scientists to gain detailed understanding of spray drying process of solid dispersion using minimal resources and time during early formulation development stage. It will also help them to ensure consistent quality of SSDs using broad range of input variables.

To evaluate the effect of addition of an anionic surfactant on solid dispersion using model drug indomethacin

Formation of solid dispersion also known as high energy solids is one of the most successful concepts to improve dissolution profile of poorly water-soluble drugs. Use of surfactants in formulation is one of the methods to increase solubility profile. In this research, we have used model drug, a weak acid (indomethacin) together with polymer (PVP) and anionic surfactant (sodium lauryl sulfate (SLS)) in different concentrations to study the effect of incorporation of SLS in solid dispersion. Three ratios and control were prepared. Physical characterization was performed using modulated differential scanning calorimetry (MDSC), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. Critical micelle concentration (CMC) measurements were conducted to see the effect of SLS on dissolution media. Dissolution studies were performed in hydrochloric acid buffer (pH 1.2 buffer), purified water and phosphate buffer (pH 7.4), respectively. Interestingly, depending upon addition of SLS into the system, release profiles were changed. SLS incorporated internally in a solid dispersion gave the highest release.

Development of Polyvinylpyrrolidone-Based Spray-Dried Solid Dispersions Using Response Surface Model and Ensemble Artificial Neural Network

A model for spray drying processes was developed using polyvinylpyrrolidone (PVP)-K29/32 as a placebo formulation to predict quality attributes (process yield, outlet temperature, and particle size) for binary solid dispersions (SDs). The experiments were designed to achieve a better understanding of the spray drying process. The obtained powders were analyzed by modulated differential scanning calorimetry, thermogravimetric analysis, X-ray diffraction, polarized light microscopy, and particle size analysis. On the basis of the experimental data, a response surface model and an ensemble artificial neural network were developed. Both models showed significant correlation between experimental and predicted data for all quality attributes. In addition, a Pearson correlation analysis, response surface curves, Kohonens self-organizing maps, and contribution plots were used to evaluate the effect of individual process parameters on quality attributes. The predictive abilities of both models were compared using separate validation datasets. These datasets contained binary SDs of four model drugs with PVP based on root mean square error and mean absolute error for each quality attribute. The results indicate that both models show reliable predictivity for all quality attributes. The present methodology provides a useful tool for designing a spray drying process, which will help formulation scientists save time, drug usage, and resources in the development of spray-dried SDs.

Development of acetaminophen proline prodrug

In this research work, proline ester prodrug of acetaminophen (Pro-APAP) was synthesized and evaluated for its stability in PBS buffer at various pH and Caco-2 cell homogenate. The Pro-APAP is more stable at lower pH than higher pH, with half-life of 120min in PBS buffer at pH 2.0, half-life of 65min at pH 5.0, and half life of 3.5min at pH 7.4, respectively. The half-life of Pro-APAP in Caco-2 cell homogenate is about 1min, much shorter than the half-life in PBS buffer at pH 7.4, indicating enzymes in the cell homogenate contribute to the hydrolysis of the ester bond. Carboxypeptidase A was incubated with Pro-APAP at pH 7.4 with half-life of 3.8min which is very close to the half life in buffer itself. This clearly indicates carboxypeptidase A is not one of the enzymes contributing to the hydrolysis of the prodrug. Physicochemical characteristics such as melting point and stability of newly synthesized prodrug were determined by MDSC technique.

Formulation and characterization of acetaminophen nanoparticles in orally disintegrating films

Abstract The purpose of this study was to prepare orally disintegrating films containing nanoparticles loaded with acetaminophen. Nanoparticles were prepared by the emulsion-solvent evaporation method where acetone phase containing acetaminophen and poly(lactide-co-glycolide acid) (PLGA) was added to water phase containing hydroxypropyl methyl cellulose, poly ethylene glycol, polyvinyl alcohol (PVA) and aspartame in a rate of 1.5 drop s−1 and agitated at 1200 rpm. The size, polydispersity index (PI) and drug entrapment (DE) were measured. The emulsions were cast to form films, which were evaluated physico-mechanically. The effect of different degrees of hydrolization of PVA and polymerization of PLGA and the effect of different ratios of PVA to PLGA was studied. Films with acceptable physico-mechanical properties were further studied. The size and PI of the nanoparticles was dependent on PVA hydrolization, PLGA polymerization and the ratio of PVA to PLGA. All films disintegrated in less than one minute, but acetaminophen was not free in the dissolution media even after six days. These results may indicate that although the nanoparticles released from the films immediately when impressed in solution the drug is sustained in the nanoparticles for longer time, which is to be clarified in future work.

Fusion Method for Solubility and Dissolution Rate Enhancement of Ibuprofen Using Block Copolymer Poloxamer 407.

ABSTRACTAim of current research was to prepare ibuprofen-poloxamer 407 binary mixtures using fusion method and characterize them for their physicochemical and performance properties. Binary mixtures of ibuprofen and poloxamer were prepared in three different ratios (1:0.25, 1:0.5, and 1:0.75, respectively) using a water-jacketed high shear mixer. In vitro dissolution and saturation solubility studies were carried out for the drug, physical mixtures, and formulations for all ratios in de-ionized water, 0.1 N HCl (pH = 1.2), and phosphate buffer (pH = 7.2). Thermal and physical characterization of samples was done using modulated differential scanning calorimetry (mDSC), X-ray powder diffraction (XRD), and infrared spectroscopy (FTIR). Flow properties were evaluated using a powder rheometer. Maximum solubility enhancement was seen in acidic media for fused formulations where the ratio 1:0.75 had 18-fold increase. In vitro dissolution studies showed dissolution rate enhancement for physical mixtures and the formulations in all three media. The most pronounced effect was seen for formulation (1:0.75) in acidic media where the cumulative drug release was 58.27% while for drug, it was 3.67%. Model independent statistical methods and ANOVA based methods were used to check the significance of difference in the dissolution profiles. Thermograms from mDSC showed a characteristic peak for all formulations with Tpeak of around 45°C which suggested formation of a eutectic mixture. XRD data displayed that crystalline nature of ibuprofen was intact in the formulations. This work shows the effect of eutectic formation and micellar solubilization between ibuprofen and poloxamer at the given ratios on its solubility and dissolution rate enhancement.

Evaluation of Hydroxypropyl Methylcellulose Matrix Systems as Swellable Gastro-Retentive Drug Delivery Systems (GRDDS)

Utilizing gastro-retentive drug delivery systems (GRDDS) to increase absorption of weakly basic drugs by extending their transit time is a promising approach. Swellable systems were evaluated for this purpose. Such systems demonstrate dual mechanism of release-diffusion and erosion. GRDDS requires maintaining its dimensions, which demands diffusion as a predominant mechanism of release (Fickian). In this work, dypyridamole, a weakly basic drug, together with various grades of hydroxypropyl methylcellulose and different excipients were evaluated for release and swelling properties. Dissolution data were analyzed by curve fitting to various models to estimate predominant release mechanism. It was found that matrices containing a swellable diluent like microcrystalline cellulose demonstrated predominantly Fickian mechanism of release, whereas soluble diluents (lactose and mannitol) contributed to a mixed mechanism of release. Addition of copovidone increased the swelling and survivability, whereas sodium chloride altered the erosion behavior. A correlation between matrix weight loss and drug release was obtained, which further consolidated the analysis. Correlation for the soluble excipients was linear, whereas that for the swellable excipient was nonlinear, implying predominance of Fickian release mechanism for the latter. Hence, the selection of excipients can influence matrix survivability and release kinetics, which can be used for developing GRDDS.

To prepare and characterize microcrystalline cellulose granules using water and isopropyl alcohol as granulating agents and determine its end-point by thermal and rheological tools

Abstract Microcrystalline cellulose (MCC-102) is one of the most commonly used excipient in the pharmaceutical industry. For this research purpose, authors have developed a different technique to determine the end point for MCC-102 using water and isopropyl alcohol 70% (IPA) as granulating agent. Wet and dry granules obtained were characterized for their flow properties using the powder rheometer and thermal analysis. Powder rheometer was used to measure basic flowability energy (BFE), specific energy (SE), percentage compressibility, permeability and aeration. Thermal analysis includes effusivity and differential scanning calorimetry (DSC) measurements. BFE and SE results showed water granules requires high energy as compared to IPA granules. Permeability and compressibility results suggest IPA forms more porous granules and have better compressibility as compared to water granules. Hardness data reveals interesting phenomena in which as the amount of water increases, hardness decreases and vice-versa for IPA. Optimal granules were obtained in the range of 45–55% w/w. DSC data supported the formation of optimal granules. Empirical measurements like angle of repose did not reveal any significant differences between powder flow among various granules. In this paper, with the help of thermal effusivity and powder rheology we were able to differentiate between various powder flows and determine the optimal range for granule formation.