SOLUBILITY ENHANCEMENT OF MODEL COMPOUNDS

Solubility is the amount of solute in the solvent system at phase equilibrium with certain temperature and pressure. Many of the new chemical entities are lipophilic molecules that require techniques to enhance solubility. Solubility enhancement can be achieved by either physical and/or chemical modification of the drug. Various techniques are available for solubility enhancement of poorly soluble drugs include particle size reduction, salt formation, solid dispersions, use of surfactants, prodrug, crystal modification, etc. In this study, the three model drugs belong to BCS class II and IV having low solubility with a certain range of physicochemical properties were studies in solubility enhancement using fusion method, co-precipitation, nano-milling and spray drying techniques. The two different polymers employed for solubility enhancement are PEG 8000 and PVP 40,000. Solubility was determined by Shake Flask method at the temperature of 37±0.1 °C. The objective is to investigate the enhancement of solubility of the three model drugs namely Glipizide, Carvedilol and Furosemide in 1:1, 1:5 and 1:10 drug-polymer ratios and are characterized by Differential Scanning Calorimetry (DSC). The Solubility of Glipizide was enhanced from 11.18 ± 1.78 µg/ml to 35.73 ± 0.04 µg/ml by 219 % increase with nano-milling technique at 1:5 ratio with PEG 8000 as carrier whereas with PVP 40000 as carrier, 286 % increase in solubility to 43.26 ± 7.87 µg/ml was observed at 1:1 ratio by fusion method. The solubility of Carvedilol was enhanced from 5.04 ± 0.55 µg/ml to 17.51 ± 0.94 µg/ml by 246 % at 1:5 ratio by fusion method with PEG8000 as carrier and 2924 % enhancement in solubility to 152.70 ± 9.09 µg/ml at 1:10 ratio by nano-milling with PVP40000 as the carrier. Furosemide showed an increase in solubility from 55.94 ± 2.48 µg/ml to 164.11 ± 9.18 µg/ml by 193 % at 1:10 ratio by nano-milling technique with PEG8000 as carrier whereas with PVP40000 as carrier, 444 % increase was observed at 1:1 ratio by nano-milling technique with solubility of 304.52 ± 23.11 µg/ml. The data showed that the decrease in percentage crystallinity and enthalpy of fusion of the model drugs upon implementing solubility enhancement techniques with the effect of particle size and the carrier used resulted in the increase of aqueous solubility of the model drugs

Formulation Development and Evaluation of Aqueous Injection of Poorly Soluble Drug Made by Novel Application of Mixed Solvency Concept

It is commonly recognized in the pharmaceutical industry that on average more than 40% of newly discovered drug candidates are poorly water-soluble. The objective of present research is to explore the application of mixed solvency technique in the injection formulation of poorly soluble drugs and to reduce concentration of individual solubilizers (used for solubility enhancement) to minimize the toxic effects of solubilizers. In the present work poorly soluble drugs Ofloxacin are selected as model drugs. Ofloxacin is an antibiotic drug tried to formulate the aqueous injection by the use of various physiologically compatible solubilizing agent like Lignocaine Hydrochloride, Niacinamide, Sodium benzoate, Sodium citrate, PEG 400, PEG 4000, PVP 40000, Ethanol, and Propylene Glycol. For expected synergistic enhancement effect on solubility of these poorly soluble drugs various blends of solubilizers shall be tried to decrease the amounts of Solubilizer employed for a desired solubility enhancement ratio. The study further opens the chances of preparing dry powders for injection of drug which are not stable in aqueous solution, ready to use injection. Key word- Mixed solvency solubilization, Ofloxacin, solubility enhancement, synergistic enhancement effect

Preparation of hydrochlorothiazide nanoparticles for solubility enhancement

Nanoparticles can be considered as a useful tool for improving properties of poorly soluble active ingredients. Hydrochlorothiazide (Class IV of the Biopharmaceutical Classification System) was chosen as a model compound. Antisolvent precipitation-solvent evaporation and emulsion solvent evaporation methods were used for preparation of 18 samples containing hydrochlorothiazide nanoparticles. Water solutions of surfactants sodium dodecyl sulfate, Tween 80 and carboxymethyl dextran were used in mass concentrations of 1%, 3% and 5%. Acetone and dichloromethane were used as solvents of the model compound. The particle size of the prepared samples was measured by dynamic light scattering. The selected sample of hydrochlorothiazide nanoparticles stabilized with carboxymethyl dextran sodium salt with particle size 2.6 nm was characterized additionally by Fourier transform mid-infrared spectroscopy and scanning electron microscopy. It was found that the solubility of this sample was 6.5-fold higher than that of bulk hydrochlorothiazide.Web of Science218art. no. 100

REVIEW ARTICLE: SOLUBILITY ENHANCEMENT BY SOLID DISPERSION

Enhancement of solubility, dissolution rate and bioavailability of the drug is a very challenging task in drug development, nearly 40% of the new chemical entities currently being discovered are poorly water soluble drugs. The solubility behaviour of the drugs remains one of the most challenging aspects in formulation development. This results in important products not reaching the market or not achieving their full potential. Solid dispersion is one of the techniques adopted for the formulation of such drugs and various methods are used for the preparation of solid dispersion. Solid dispersion is generally prepared with a drug which is having poor aqueous solubility and hydrophilic carrier. This article review various methods and concept of solid dispersion, criteria for drug selection, advantage and disadvantage, characterization, and application

Solubility Enhancement of Atorvastatin Calcium Using Cyclodextrin

The present study is intended to increase the solubility and dissolution rate of Atorvastatin calcium (ATN Ca) by formulating the drug- hydroxy-propyl-beta cyclodextrin (HPBCD) complexes using solvent-assisted extrusion (SAE) using a twin-screw extruder. Various studies on ATN Ca saturation solubility in water and other pH mediums revealed a pH-dependent solubility with a difference. Thus, the saturation solubility for ATN Ca and Solvent Assisted Extruded complex was conducted in water and different pH mediums in this study. Phase solubility studies between ATN Ca and CDs revealed an AL-type solubility profile exhibiting a linear increase with HPBCD. Drug-HPBCD complexes were made using the solvent-assisted extrusion (Twin Screw Extruder) procedure and conventional techniques, including physical mixing and the kneading method. The solubility of the SAE complexes, as compared to normal ATN Ca (0.0167 mg/mL), was 0.294 mg/mL, respectively. Differential scanning calorimetry and Fourier transform infrared spectroscopy analyses were used to confirm the formation of drug-cyclodextrin inclusion complexes. The formulated products were filled into #2 clear gelatin capsules for better dissolution. According to tests on drug release at 5 min, 10 min, 15 min, and 30 min time intervals, ATN Ca was released at the highest rate from solvent-assisted extruded complex (103 %) compared to other samples. When compared to the drug release from complexes formed by kneading was much lower (89 %). All these studies show promising results to conclude that the complex formed through solvent-assisted extrusion (SAE) has enhanced the solubility and dissolution rate of the Atorvastatin Calcium

Co-amorphization of olanzapine for solubility enhancement

Communication presented at the 3rd International Congress of CiiEM - Research and Innovation in Human and Health Sciences. Monte da Caparica, Portugal, 20-22 June 2018N/

SOLUBILITY ENHANCEMENT OF NORFLOXACIN BY HYDROTROPY TECHNIQUE

The objective of this study is to improve the solubility of poorly water soluble anti-bacterial drug Norfloxacin by hydrotropic solubilization technique. For the present study sodium benzoate was used as hydrotropic agent. By using this hydrotropic agent as water soluble carrier, hydrotropic solid dispersions of Norfloxacin were prepared.in 1:1, 1:2, 1:3 and 1:4 ratios (drug: hydrotropic agent). Equilibrium solubilization of pure drug and hydrotropic solid dispersions of Norfloxacin in distilled water by excess solute method and solubility enhancement ratios were calculated by measuring the absorbance of the solutions at 274.80 nm using UV spectrophotometer. The hydrotropic agent did not interfere in analysis. The results showed that there was an increase in the solubility of Norfloxacin with hydrotropic solid dispersions compared to pure drug in distilled water. There was 9.56 fold enhancement in aqueous solubility of Norfloxacin with hydrotropic solid dispersion of 1:4 ratio compared to 1:1 (6.29), 1:2 (7.09) and 1:3 (8.59) ratios

SOLUBILITY ENHANCEMENT OF POORLY WATER SOLUBLE DRUGS

Aqueous solubility is a limiting factor in the oral bioavailability of a certain class of poorly water soluble drugs. A consequence of low aqueous solubility is a slow dissolution rate. For the drugs with low aqueous solubility and high permeability the dissolution rate will be the rate limiting step for absorption. The most successful techniques that are employed for dissolution enhancement are micronization, formulation of amorphous systems and cyclodextrins containing dosage forms. This combined approaches to improve the dissolution of some poorly soluble drugs. Micronization increases the dissolution rate of drugs through increased surface area. The high surface area of drug micro/nano particles renders them thermodynamically unstable, promoting agglomeration and crystal growth. Microparticles of the poorly water soluble drugs were produced by the supercritical antisolvent method and simultaneously mixed with pharmaceutical excipients in a single step to prevent the drug agglomeration of drug particles. In the third approach cyclodextrins (CDs) were used as pharmaceutical solubilizers and inclusion complexes of drugs with β-CD.Key words: micronization, supercritical antisolvent, cyclodextrin

SOLUBILITY ENHANCEMENT OF LURASIDONE HYDROCHLORIDE BY PREPARING SMEDDS

Objective: The objective of the study was to enhance solubility of Lurasidone HCl, an atypical antipsychotic drug, by formulating self-micro emulsifying drug delivery system (SMEDDS) and its characterization.Methods: Solubility study of Lurasidone hydrochloride (LH) was carried out in various surfactants, co surfactants and oils. Pseudo ternary phase diagrams were constructed to identify the self-micro emulsification region. Screening was done so as to determine the proper combination of components. Based on this, LH SMEDDS were prepared using Cremophor RH40 (surfactant), Soluphor P (co-surfactant) and Capmul MCM (oil). The preconcentrate SMEDDS were evaluated for clarity(visual), precipitation, % transmittance, robustness to dilution, freeze thawing, particle size distribution and zeta potential and adsorbed SMEDDS were evaluated for drug content, flow properties, in-vitro dissolution and ex-vivo diffusion studies.Results: The optimized LH SMEDDS composed of 14% Cremophor RH40, 68% Soluphor P, 18% Capmul MCM with a particle size of 3.95 µm and zeta potential of more than 50 mV showing 80% dissolution in 60 min.Conclusion: The results of this study prove that SMEDDS help in improving the solubility, dissolution and bioavailability of lurasidone hydrochloride.Â

Selection of hydrotropes for enhancing the solubility of artemisinin in aqueous solutions

Artemisinin is an antimalarial substance very sparingly soluble in water. In the attempt to identify environmental-friendly and non-toxic aqueous-based solvents to extract it from Artemisia annua L., the solubility of artemisinin in aqueous solutions of different hydrotropes was measured at 303.2 K, for hydrotrope concentrations up to 5 M. The ability of the studied hydrotropes for enhancing the artemisinin solubility increases in the following order: Na[N(CN)2] < Na[SCN] < [Chol][Van] < [Chol][Gal] < [N4,4,4,4]Cl < [Chol][Sal] < [P4,4,4,4]Cl < Na[Sal], with Na[Sal] allowing an increase in the solubility of 750 fold compared to pure water. The COSMO-RS model and experimental Kamlet-Taft solvatochromic parameters were applied to connect the solubility enhancement with solvent properties. At low hydrotrope concentration, the solubility increases with the decreasing of the difference between the Apolar Factors of the hydrotrope and artemisinin, while for higher hydrotrope concentration, the hydrogen-bond acceptor character of the hydrotrope seems to have an impact on the solubility enhancement. Even if some mechanistic understanding is still to unfold, quantitatively the empirical correlations of solubility enhancement with the hydrotrope concentration and the solvatochromic parameters show very high accuracy. In particular, 93% of the change on the artemisinin solubility enhancement could be explained using the hydrotrope concentration and two combined solvatochromic parameters (αβ and π∗2) as explaining variables.This work was developed within the scope of the projects CICECOAveiro Institute of Materials, UIDB/50011/2020 & UIDP/50011/2020, CIMO-Mountain Research Center, UIDB/00690/2020, and Green Health (Norte-01-0145-FEDER-000042) all financed by national funds through the FCT/MEC and when appropriate co-financed by FEDER under the PT2020 and NORTE 2020 Partnership Agreement. Isabela Sales and Silvana Mattedi thanks the finantial support from CAPES and CNPq/ Brazil (CAPES: Proc. 88881.189075/2018-01 and 88887.494428/2020- 00. CNPq: Grant 303089/2019-9 and Proc.438036/2018-2).info:eu-repo/semantics/publishedVersio