Saturation Solubility Of Drug Research Articles

Formulation Development and Evaluation of Oro-Dispersible Tablets Based On Solid Dispersion of Cimetidine

The most common problem about conventional dosage form is dysphagia (difficulty in swallowing). So, we design a new approach in a conventional dosage form which is oral dispersible tablet. Oral dispersible tablet is also called as mouth dissolving tablet, fast dissolving tablet, or oral disintegrating tablet. Oral dispersible tablet has advantage as it quickly disintegrates into saliva when it is put on the tongue. The faster the drug disintegrates or is dissolved, the faster the absorption and the quicker the therapeutic effect of drug will be attained. The objective of present study was to formulate directly compressible orodispersible tablets of cimetidine with improved solubility and bioavailability by using solid dispersion technique. Cimetidine is a histamine H2-receptor antagonist. It is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome, gastroesophageal reflux disease and erosive esophagitis. Solid dispersion of cimetidine was prepared by anti-solvent addition method and physical mixture using novel polymer eudragit E 100. Saturation solubility of drug was determined in physical mixture and solid dispersion formulation. The prepared solid dispersion formulations were further characterized by drug contents, HPLC, and encapsulation efficiency. Orodispersible tablets of cimetidine were prepared by direct compression method and blend was evaluated for the pre-compression parameters such as bulk density, compressibility, angle of repose etc. The tablets were prepared by using selected solid dispersion formulation and excipients with sodium starch glycolate as a superdisintegrant and evaluated for hardness, friability, weight variation, content uniformity, wetting time, dispersion time and in-vitro drug release. Orodispersible tablet shows wetting time 27±1 seconds and in-vitro drug release 93.20±3.181%, which is better as compare to tablet containing pure drug (82.36±1.986) within 20min. Thus formulation of orodispersible tablet of cimetidine solid dispersion showed increased solubility and bioavailability with patient complies and convenience.
 Keywords: Cimetidine, Orodispersible tablets, Solid dispersion, Anti solvent addition method, Superdisintegrant

Robust Wet Milling Technique for Producing Micronized Ibuprofen Particles with Improved Solubility and Dissolution

This study investigated a systematic approach for producing ibuprofen (IBF) particles with leucine by wet milling. Using a high shear homogenizer, the particles size of the IBF was reduced. Prepared IBF microparticles were freeze-dried and characterized by using Mastersizer, SEM, DSC, XRD, ATR-FTIR, and TGA. The drug saturation solubility and in-vitro dissolution performance were carried out in phosphate buffer solution (PBS, pH 7.4) at 37°C temperature and IBF were determined using a validated HPLC method. The wet-milled method reduced the particle size from 71.3 to 1.7μm. The minimum particle size of IBF was obtained in 0.05% Tween 80 solution homogenized at 17,000rpm for 15min. The saturated solubility (168.7µg/mL) of the micronized IBF particles with leucine showed higher compared to that of the original IBF (147.4µg/mL) in PBS solution. The prepared IBF particles containing 2.5-6.25% leucine showed significantly higher IBF release (100%) compared to that of original drug particles (55.9%) in 120min. The excipient leucine played a major role in enhancing the solubility and dissolution profile of the prepared IBF particles probably by the formation of hydrogen bonding. The developed wet milling was an efficient and robust technique for reducing the particle size of IBF and could be a useful method for manufacturing drug particles with enhanced solubility and dissolution.

Phase-Field Model for Drug Release of Water-Swellable Filaments for Fused Filament Fabrication.

This paper treats the drug release process as a phase-field problem and a phase-field model capable of simulating the dynamics of multiple moving fronts, transient drug fluxes, and fractional drug release from swellable polymeric systems is proposed and validated experimentally. The model can not only capture accurately the positions and movements of the distinct fronts without tracking the locations of fronts explicitly but also predict well the release profile to the completion of the release process. The parametric study has shown that parameters including water diffusion coefficient, drug saturation solubility, drug diffusion coefficient, initial drug loading ratio, and initial porosity are critical in regulating the drug release kinetics. It has been also demonstrated that the model can be applied to the study of swellable filaments and has wide applicability for different materials. Due to explicit boundary position tracking being eliminated, the model paves the way for practical use and can be extended for dealing with geometrically complex drug delivery systems. It is a useful tool to guide the design of new controlled delivery systems fabricated by fused filament fabrication.

Design space approach in the development of esculetin nanocrystals by a small-scale wet-bead milling process

Esculetin, a natural coumarin derived from herbs, has shown different potential pharmacological activities. However, the poor aqueous solubility of esculetin may limit its therapeutic efficacy. Nanocrystal is a promising dosage form to overcome this drawback by enhancing drug saturation solubility. Hence, a laboratory-scale wet-bead milling approach was employed to develop an esculetin nanocrystal formulation. Povacoat™ was selected as a stabilizer after screening different surfactants and polymers. Design of experiments was applied to identify and understand the relationship between process parameters and formulation compositions at the stage of formulation optimization. Furthermore, the optimized formulation was solidified using two different approaches (spray-drying and freeze-drying) and characterized by dynamic light scattering, laser diffraction, transmission electron microscopy, scanning electron microscopy, thermal analysis, and X-ray powder diffraction. An esculetin-Povacoat™ nanocrystal formulation that maintained a 200 nm particle size for 180 days was successfully obtained with specific critical process parameters and formulation composition within the design space.

SOLID DISPERSION TECHNIQUE TO ENHANCE THE SOLUBILITY AND DISSOLUTION OF FEBUXOSTAT AN BCS CLASS II DRUG

Objective: The present study was aimed to enhance the solubility of poorly water-soluble drug (BCS Class II) Febuxostat using water-soluble polymers.Methods: Pre-formulation studies like drug excipient compatibility studies by Fourier-transform infrared spectroscopyDifferential scanning calorimetry and determination of saturation solubility of drug individually in various media like distilled water and pH 7.4 phosphate buffer. Solid dispersions of Febuxostat was prepared using Polyethylene glycol (PEG 6000) (fusion method) and Polyvinyl pyrrolidone (PVP K30) (solvent evaporation method) in various ratios like 1:1, 1:2, 1:3 and 1:4 separately. The formulated solid dispersions were evaluated for percentage yield, drug content and in vitro dissolution studies.Results: From the results of pre-formulation studies it was revealed that there was no interaction between drug and excipients and the pure drug was poorly soluble in water. The percentage yield of all formulations was in the range of 54-78 %, and drug content was in the range of 43-78 mg. The solid dispersion containing polyvinylpyrrolidone K 30 in 1:4 ratio showed the highest amount of drug release at the end of 30 min than other formulations.Conclusion: Finally it was concluded that solid dispersion prepared with PVP K-30 in 1:4 ratio by solvent evaporation method was more soluble than by fusion method.

In-vitro study of formulation and evaluation of nanosuspension of tamoxifen

Background: Nanosuspension technology has been developed as a promising candidate for efficient delivery of hydrophobic drugs. It could maintain the required crystalline state of the drug with reduced particle size, leading to an increased reporting on dissolution rate and therefore improved bioavailability.Methods: In this paper, we report on the preparation of Tamoxifen nanosuspension by high-pressure homogenization (HPH). The aim is to obtain a stable nanosuspension with an increased drug saturation solubility and dissolution velocity. The morphology and particle size distribution of the modified nanosuspensions were characterized by the means of several analyses that included: transmission electron microscopy (TEM), polarized light microscopy (PLM), scanning electron microscopy, differential scanning calorimetry (DSC) and powder X- ray diffractometry (XRD).Results: HPH was employed to produce aqueous drug nanosuspensions with fine solubility and dissolution properties, which render the produced particles stable up to one month. In addition, the prepared nanosuspensions possessed a high drug-loading efficiency (10%). The recoded zeta potential values (≈ -27 mV) indicated that the prepared nanosuspensions possess a higher degree of long-term stability. TEM data showed narrow size distribution with average size 322.7 nm. Morphologically, as indicated from results, the produced nanosuspensions have a homogenous distribution even after redispersion, indicating the stability of the product.Conclusions: It was possible to obtain Tamoxifen nanosuspensions with fine solubility and dissolution properties. Nanosuspensions possessed a high drug- loading (10%), which could reduce the dosage administration and gastrointestinal side effects. HPH can be employed to produce aqueous drug nanosuspensions that are stable up to one month. Aqueous nanosuspension can be converted to dry nanocrystals by lyophilization which offer superior physicochemical properties.

Large-scale preparation of stable irbesartan nanoparticles by high-gravity liquid antisolvent precipitation technique

Irbesartan (IBS), an angiotensin II receptor antagonist mainly used for the treatment of hypertension, is a poorly water-soluble drug. To enhance its solubility and dissolution rate, and thus potentially improve the oral bioavailability, stable amorphous IBS nanoparticles were prepared via high-gravity liquid antisolvent precipitation (HGLAP) technique, without requiring any additives. The effect of various operating parameters on particle size was investigated in detail. IBS nanoparticles with an average size of 295nm were successfully prepared. Compared to the raw drug, the saturation solubility of IBS nanoparticles was dramatically increased from 3.6μg/mL to 13.7μg/mL. The prepared nanoparticles exhibited a good stability and were capable of generating a maximum supersaturation level, reaching up to ∼13.5 times of raw drug's saturation solubility. In vitro dissolution test, IBS nanoparticles showed a significantly enhanced dissolution rate and 100% of the drug dissolved within 30min, while the raw drug did not dissolve completely even after 120min. HGLAP technique offers a great opportunity for the massive production of drug nanoparticles with improved solubility and dissolution rate.

Formulation and Characterization of Solid Self- Microemulsifying Cefuroxime Axetil Products

The Cefuroxime axetil has been used in treatment of wide range of infections but exhibits poor and variable bioavailability thus it is difficult to establish optimal oral dosage schedule. The purpose of this work was to prepare stable solid self-microemusifying drug delivery system (S-SMEDDS) of cefuroxime to improve the solubility and dissolution. The saturation solubility of drug in oils, solvents, surfactants and co-surfactants were determined and ternary phase diagram was drawn. Based on the results SMEDDS were prepared and characterized for self-emulsification properties and in-vitro dissolution. One of the best SMEDDS formulations was converted to S-SMEDDS by adsorption technique using maltodextrin as adsorbent. SEM of the S-SMEDDS revealed that particles were well separated and were free flowing, characterization by DSC, XRD revealed no interaction between drug and excipients. In-vitro dissolution was rapid and complete and no marked changes in physical and emulsification property were observed on stability.

Dissolution Studies of Poorly Soluble Drug Nanosuspensions in Non-sink Conditions

Sink conditions used in dissolution tests lead to rapid dissolution rates for nanosuspensions, causing difficulties in discriminating dissolution profiles between different formulations. Here, non-sink conditions were studied for the dissolution testing of poorly water-soluble drug nanosuspensions. A mathematical model for polydispersed particles was established to clarify dissolution mechanisms. The dissolution of nanosuspensions with either a monomodal or bimodal size distribution was simulated. In the experimental part, three different particle sizes of indomethacin nanosuspensions were prepared by the wet milling technique. The effects of the dissolution medium pH and agitation speed on dissolution rate were investigated. The dissolution profiles in sink and non-sink conditions were obtained by changing the ratio of sample amount to the saturation solubility. The results of the simulations and experiments indicated that when the sample amount was increased to the saturation solubility of drug, the slowest dissolution rate and the best discriminating dissolution profiles were obtained. Using sink conditions or too high amount of the sample will increase the dissolution rate and weaken the discrimination between dissolution profiles. Furthermore, the low solubility by choosing a proper pH of the dissolution medium was helpful in getting discriminating dissolution profiles, whereas the agitation speed appeared to have little influence on the dissolution profiles. This discriminatory method is simple to perform and can be potentially used in any nanoproduct development and quality control studies.

Formulation and optimization of desogestrel transdermal contraceptive patch using crystallization studies

Levonorgestrel (LNG) is the most commonly used progestin in contraception. In this study, we report the use of an alternative progestin, desogestrel, for transdermal contraception. The drug was found to be significantly more permeable as compared to LNG (p<0.05). Crystallization studies were used to select the best adhesive among acrylate (Duro-Tak 87-4098 and Duro-Tak 87-202A) and polyisobutylene (PIB, Duro-Tak 87-608A) pressure sensitive adhesives by determining the drug's saturation solubility in them. The use of copovidone and mineral oil as formulation excipients was investigated to increase drug loading in the PIB adhesive. Physical characterization of the patches was performed using in vitro drug release, content analysis, patch weight and thickness variations and rolling ball tack and peel adhesion studies. Optimized patches were evaluated for in vitro transdermal delivery across hairless rat skin. The saturation solubility of desogestrel was found to be approximately 49.3% (w/w) and 55.6% (w/w) in Duro-Tak 87-4098 and Duro-Tak 87-202A acrylate adhesives, respectively. The saturation solubility of desogestrel was significantly lower (3-4%, w/w) in the PIB adhesive. Mineral oil (10%, w/w) and copovidone (30%, w/w) were found to be optimum for increasing drug loading and patch cosmetics. Results from the physical characterization studies suggest that a uniform and reproducible 7 day drug-in-adhesive patch could be developed.

Development of an Oral Curcumin Nanocrystal Formulation

During the last ten years, the formulation of drugs as nanocrystals has rapidly evolved into a mature drug delivery strategy, with currently five products on the market. The major characteristic of these systems is the rapid dissolution velocity, enabling bioavailability enhancement after oral administration. This study describes the preparation of a solid dosage capsule form of spray-dried curcumin nanocrystal and compares its dissolution behavior with market capsule in different media. The aim was to obtain a stable nanocrystal loaded drug capsule with an increased drug saturation solubility and dissolution velocity. The solubility and dissolution experiments were performed to verify the obvious improvement of the dissolution behavior compared with commercial product. Improved dissolution behavior in drug nanocrystal-loaded solid dosage forms should lead to better bioavailability of poorly soluble drugs in the body.

Assessment of a Five-Layer Laminate Technique to Measure the Saturation Solubility of Drug in Pressure-Sensitive Adhesive Film

A five-layer laminate technique is used to determine the saturation solubility of a drug in a thin polymer film, c(p)(s), of pressure-sensitive adhesive (PSA) used to prepare transdermal patches. A drug-loaded donor polymer film is attached via a separating membrane to an initially drug-free acceptor polymer film. Diffusion of drug occurs into the acceptor up to saturation solubility equilibrium. This systematic study of the technique using the drug tamsulosin and the PSA Duro Tak 87-4098 was a kinetic analysis of the diffusion process. It was found that the technique gives an equilibrium value for c(p)(s) in a PSA polymer film in the presence of crystalline phase of the drug in the donor. A highly permeable Perthese-separating membrane caused overshoot in the acceptor, most likely induced by initial supersaturation of the donor. Change to a less-permeable ethylene-vinyl-acetate-separating membrane avoided overshoot, but gave a prolonged time, >300 days, to equilibrium. Preloading the acceptor accelerated the equilibration process to approximately 50 days with the Perthese. Suitable experimental conditions are identified that, if performed correctly, allow the technique to give an equilibrium value for c(p)(s).

Preparation and Characterization of an Oridonin Nanosuspension for Solubility and Dissolution Velocity Enhancement

This study describes the preparation of an oridonin (ORI) nanosuspension by high-pressure homogenization (HPH). The aim was to obtain a stable nanosuspension with an increased drug saturation solubility and dissolution velocity. The homogenization procedure was optimized in regard to particle size and long-term stability. The characteristics of the oridonin nanosuspension, such as particle size, size distribution, shape, and zeta potential, were evaluated following the water removal. The solubility and dissolution experiments were performed to verify the obvious improvement of the dissolution behavior compared with commercial ORI. Finally, crystalline state evaluation before and following the formulation was performed through differential scanning calorimetry (DSC) and powder X-ray (PXRD).

Influence of micro-environmental pH on the gel layer behavior and release of a basic drug from various hydrophilic matrices

The purpose of this investigation is to understand the influence of gastrointestinal (GI) pH on the gel layer formation and its dynamics for various hydrophilic/swellable matrices, in the process of developing a pH-independent controlled release system for a basic drug, oxybutynin hydrochloride (OXB). Cylindrical matrices (8-mm diameter) without and with fumaric acid, were readily prepared by direct compression. Formulations were evaluated for in vitro drug release, and gel layer dynamics was studied by viscosity measurements and texture profiling analysis. In the in vitro drug release study, OXB, which shows pH-dependent solubility, showed faster release from all the matrices in pH 1.2 medium. Release rates enhanced to a lesser extent with change of medium from pH 6.8 to pH 1.2, for HPMC polymer matrices. Anionic polymer matrices showed drastic differences in the release rates when medium was changed from pH 6.8 to pH 1.2. Addition of fumaric acid to matrices demonstrated pH-independent drug release, which was attributed to the micro-environmental pH manipulation within the hydrated gel layer. Viscosity and texture profiling studies revealed that saturation solubility of drug at swelling front play a major role in the pH-dependent drug release from HPMC matrices, while both saturation solubility and the altered gel consistency as a function of pH are involved with anionic polymer matrices. Presence of fumaric acid in HPMC matrices showed efficient retardation and pH-independent drug release. In conclusion, understanding the influence of GI physiological pH on the gel layer dynamics and manipulating the micro-environmental pH provides efficient and predictable in vivo performance from these swellable cylindrical matrices.

Optimization of topical therapy: partitioning of drugs into stratum corneum.

To optimize a topical formulation for therapeutic effect generally implies that the flux of drug into the skin be maximized. This requirement means that the product of drug concentration in the vehicle (Cv) and drug partition coefficient (PC) between stratum corneum (SC) and vehicle be as large as possible. While Cv is a formulation variable which can be easily manipulated up to the drug's saturation solubility, PC is a parameter that is difficult to predict a priori. However, there is no question that an ability to evaluate PC would greatly facilitate the efficient screening of drugs and formulations. We have measured the SC/water and SC/isopropylmyristate (a model lipophilic vehicle) PCs of seven drugs; acitretin, progesterone, testosterone, diazepam, estradiol, hydrocortisone, and caffeine, SC/water PCs were determined as a function of the following variables: (i) initial drug concentration in the vehicle, (ii) length of equilibrium, (iii) SC source and preparation technique, and (iv) SC delipidization. The data obtained were reproducible and physicochemically consistent, and they show that useful partitioning information from both aqueous and nonaqueous vehicles can be obtained with the biological tissue of greatest relevance. The SC/water PCs of the steroids were in reasonable agreement with previous measurements. A facile approach to an integral determinant of formulation optimization is suggested, therefore, by these observations.