The solubility of the drugs was determined by the shake flask method 113 . Solubility study of drugs were done in four different medium 0.1N HCl, acetate buffer pH 4.5,Phosphate buffer pH 6.8, Phosphate buffer pH7.4 and distilled water. According to this method the compound is added in surplus to medium and shaken on an orbital shaker upto24 hr. The saturation is confirmed by the observation of the presence of un-dissolved material. After filtration of the slurry a sample analysis can be done. Both filtration and analysis should be performed under the same temperature as the solubility determination to minimize loss of volatile components. The amount of solute contained in the sample is determined by UV spectroscopic method. Solubility of the drug substance is expressed in mg/ml. USP suggests according to the solubility study the drugs can be categorized as,
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Polymeric nanoparticles can encapsulate drugs and release them at sustained rates in the optimal range of drug concentration, thus enhancing the in vivo therapeutic efficacy, maximizing patient compliance, and facilitating the use of highly toxic, poorly soluble, or relatively unstable drugs 10-11 . Biodegradable polymer: A polymer that loses its weight over time in the living body is called an absorbable, resorbable, or bioabsorbable polymer as well as biodegradable polymer regardless of its degradation mode for both enzymatic and no enzymatic. In other words biodegradable polymers are defined as those which are degraded in biological environment not through thermal oxidation, photolysis, or radiolysis but through enzymatic or non-enzymatic hydrolysis 12 .
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3. Nanosuspension for topical/dermal drug delivery Dermal nanosuspensions are mainly of interest if conventional formulation approaches fail.The nanocrystalline form leads to an increased saturation solubility of the drug in thetopical dosage form, thus enhancing the diffusion of the drug into the skin. The increased saturation solubility leads to “supersaturated” formulations, enhancing the drug absorption through the skin. This effect can further be enhanced by the use of positively charged polymers as stabilizers for the drug nanocrystals. The opposite charge leads to an increased affinity of the drug nanocrystals to the negatively charged stratum corneum. Among the various strategies for enhancing dermal application, nanocrystals can be considered a rather new but highly interesting approach 13,14 .
BCS class II weak basic drugs such as ketoconazole, dipyridamole, and carvedilol, easily dissolve in gastric pH and then may occur the precipitation or reach the supersaturation entering the duodenum due to higher environmental pH. In vivo drug precipitation has been a major issue facing poorly soluble drugs, especially weak bases. For this enhanced intestinal absorption to take place, supersaturation must be obtained and maintained in the gastrointestinal environment 7 . In vivo induction of supersaturation can be achieved through various formulation approaches. There are different approaches to induce supersaturation. The metastable state of supersaturation has to be sustained for a time period sufficiently long in order to improve intestinal absorption. It has been demonstrated that application of functional excipients (polymers, surfactants, etc.) can effectively minimize and/or delay drug precipitation in a highly supersaturated state and this stabilizes supersaturation as evidenced by appropriate in vitro tests. As it can be expected that the gastrointestinal environment induces drug precipitation in vivo, in vitro evaluation of supersaturation requires careful consideration of bio relevant test methods mimicking physiological environments 14 .
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A novel directly compressible (DC) co-processed excipient with improved functionality and masking the undesirable properties of individual excipients was developed without any chemical modification by using simple laboratory technique. For the development of co-processed excipient, release retarding polymers such as Polyethylene oxide (Polyox ® WSR 301) and hydroxyl propyl methyl cellulose (Methocel ® K4M) were used. Co-processed excipient was prepared in polymers weight ratio of 1:9 to 9:1 by roller compaction technique. Co-processed excipient prepared from polymers ratio of 7:3 and 8:2 showed good physico-chemical properties. The developed DC grade co-processed excipient was characterized for DSC, FTIR, SEM, XRD which confirms the absence of any chemical changes during co-processing. Highly water soluble Metoprolol succinate and poorly water soluble anhydrous Theophylline was used as model drugs for Invitro release study. Formulations prepared using co-processed excipient showed sustain drug release in which initial burst release was controlled by polyethylene oxide and HPMC controls the extended drug release. Developed formulations were kept for stability study for three month as per ICH guidelines and found to be stable. Study indicates that use co-processed excipient has added advantage over polymer with single property and can be used in sustain release formulation irrespective of drug type.
highly dependent on the physicochemical properties of the compounds and their miscibility in the molten state. There is a potential that the API, the polymer or both may degrade if excessively high temperature is needed in the melt extrusion process, especially when the melting point of the API is high. Just like in the traditional fusion process, miscibility of drug and matrix can be a problem. High shear forces resulting in high local temperature in the extruder is a problem for heat sensitive materials. However, compared to the traditional fusion method, this technique offers the possibility of continuous production, which makes it suitable for large-scale production. This report details a novel method where the API was first converted to an amorphous form by solvent evaporation and then melt-extruded with a suitable polymer at a drug load of at least 20% w/w. By this means, melt extrusion could be performed much below the melting temperature of the drug substance It has been reported that melt extrusion of miscible components results in amorphous solid solution formation, whereas extrusion of an immiscible component leads to amorphous drug dispersed in crystalline excipients. The process has been useful in the preparation of solid dispersions in a single step. Solvent evaporation 27 : This method works best for water insoluble drugs. The solvent evaporation method provides good encapsulation efficiency and produces amorphous form of compound, which gave better solubility and dissolution than its crystalline form. Like required quantity of drug dissolved in suitable solvent (like Methanol for nitrezepam), then added to polymer by stirring & melted into water- bath (50-600C). This mixture was kept in water-bath until solvent gets evaporated. Afterward it was cooled to room temperature & pass through sieves as per requirement.
cosolvents. Co-solvents are mixtures of water and one or more water miscible solvents used to create a solution with enhanced solubility for poorly soluble compounds. Co- solvent formulations of poorly soluble drugs can be administered orally and parenterals. The pharmaceutical form is always liquid. Poorly soluble compounds which are lipophilic or highly crystalline that have a high solubility in the solvent mixture may be suited to a co-solvent approach. Commonmly used cosolvents Glycerol, propylene glycol, PEG 400, Dimethyl Sulfoxide, Dimethyl Acetamide, Ethanol, n- Octanol are the commonly used cosolvents.
From the release pattern of formulations containing HPMC and Carnauba wax it could be concluded that, the combination of these polymers worked well. HPMC K 100M reported gelling agent as well as sustained / controlled release agent, for decreased initial burst release wax is used for avoiding the penetration of water and sodium alginate as disintegrating agent. The 2 3 factorial designed batches were formulated and in vitro drug release was studied. The formulation batches from F1 to F8 is evaluated for the in-vitro drug release and found that the batch F3-F8 gives optimum release and batch F7 is selected for optimization with lower polymer content.
Solubility is that the essential factor in the drug effectiveness, ability of the route of administration. Broad and proportion of freshly is discovered within the drug is water-insoluble and so poorly bioavailability contributing to desert development creation. Nanosuspension could be appeared as a promising strategy for the economical delivery of deliquescent drugs a result of them are versatile options and distinctive advantages. The down grading of the medication particles into a submicron go prompts a noteworthy increment in the disintegration rate; thus upgrades bioavailability of the nanosuspension and they contain sub microns and blend scattering of the pharmaceutically dynamic fixing particles. During a fluid part stable by wetter nanosuspension is conveyed by an oral channel respiratory organ and visual course of the organization during the investigation is focused on totally various methods for arrangement with benefits and negative mark portrayal properties application.
Hydrotropes are a diverse class of a chemical compound first describe by Neuberg (1916) that cause several fold increase in water solubility of sparingly soluble drugs. It is process in which large amount of secondary solute is added and it improves the solubility of water insoluble drugs. These additives are referred as “salting in” and “salting out”. Hydrotropes are characterizing by an amphiphilic molecular structure i.e. They consist of a hydrophilic part and a hydrophobic part (like surfactants) and also contain saturated hydrocarbon ring and ionic moiety. Hydrotropy is referred as salting in of non- electrolytes which are highly water soluble called as “hydrotropic salts” and a phenomenon known as “hydrotropism”. Mechanism involved in hydrotropy is a complexation in which interaction between lipophilic drug and hydrotropic agents such as urea, resorcinol, nicotinamide, sodium benzoate, caffeine, sodium cumenesulfonate, pyrogallol, sodium alginate, sodium citrate, sodium acetate etc. Hydrotropic agents can be used for the tritremetric analysis of BCS class 2 drugs.eg.Ketoprofen is analysed by using sodium citrate as hydrotropic agent. Hydrotropy is also called as type of co-solvency. The main advantagesof this method is that it does not require chemical modification of hydrophobic drugs, use of organic solvents, or preparation of emulsion system. 
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Another highly investigated system is dextran-cholic acid. Cholic acid is one of the major bile acids that help to deliver and digest hydrophobic fats in the human small intestine via bile acid self-aggregates. Early dextran-cholic acid systems had low stability, as indicated by a high CMC value (0.02-0.2g/ml) . A high CMC was suggestive of low thermodynamic stability . Later on, some workers [46, 47] used periodate-oxidized dextran to enhance the stability of micellar system. The free aldehyde groups generated after partial oxidation and the remaining hydroxyl groups on dextran moiety could form hydrogen bonds and thus afforded stability to the systems. Moreover, the micelles sustained the drug release up to 14 days at acidic and neutral condition and thus served as good depots for the hydrophobic drug indomethacin (~0.299mg drug/mg micelles). More recently, dextran sulfate-cholic acid was investigated to deliver superoxide dismutase (SOD) orally . They reported that SOD-loaded dextran sulfate-cholic acid had a high stability against the acidic environment of the stomach and the release of SOD in the small intestine was controlled up to 100h. Furthermore, dextran sulfate-cholic acid facilitated SOD cellular uptake, suggesting that cholic acid enhanced the interaction of micelles with the intestinal membrane. Other micellar systems were also developed by grafting polycaprolactone , poly (L-lactide) , polystyrene , lauryl group , and methyl
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Solubilization of poorly water soluble drugs has been a very important issue in screening studies of new chemical entities as well as in formulation research. In the present investigation, mixed-solvency approach has been utilized for solubility enhancement of poorly water-soluble drug, Naproxen and Furosemide (as model drugs). Sixteen blends (having total 40% w/v strength) containing various solubilizers among the commonly used hydrotropes (urea, sodium benzoate and sodium citrate), cosolvents (glycerin, ethanol, propylene glycol, PEG 600 and PEG 400) and water-soluble solids (PEG 4000 and PEG 6000) were made to study the influence on solubility of Naproxen and Furosemide individually. Most of the blends were found to increase the solubility of both drugs. This approach shall prove a boon in pharmaceutical field to develop various formulations of poorly water-soluble drugs by combining various water-soluble excipients in safe concentrations to produce a desirable aqueous solubility of poorly water- soluble drugs.
forms. Furthermore, four polymers have different properties in nature and charges, even though they were soluble in ethanol. PVP is cationic, hydrophilic and soluble in water (Oh et al. 2011). HPMC, a cellulose derivative, is neutral, hydrophilic and soluble in water (Lim et al. 2010; Park et al. 2009). Carbopol, a polyacrylic acid derivative polymerized without crosslinking agent, is anionic, hydrophilic and water-swellable(Kang et al. 2012; Yoshida et al. 2012). Ethylcellulose, a cellulose derivative, is neutral, hydrophobic and insoluble in water (Hernandez et al. 1994; Kim et al. 2011). The fenofibrate-loaded nanoparticles composed of fenofibrate and various polymers at the weight ratio of 1:1 were prepared with four different polymers.
Ketoprofen was selected in this study, as a model hydrophobic drug. Ketoprofen [2-(3-benzoylphenyl) propionic acid] is NSAID, widely used for reducing in lammation and pain caused by rheumatoid arthritis, osteoarthritis, spondylitis or abdominal cramp associated with menstruation. It is classi ied as class II drug of Biopharmaceutical Classi ication System. It has low water solubility and hence, poor dissolution rate, so to enhance its solubility and dissolution rate SDs of Ketoprofen were formulated and developed, by solvent evaporation technique, using novel and potential carrier Glucosamine HCl. Glucosamine HCl was chosen as a carrier, because it is non-toxic, highly hydrophilic and moreover, it has been used for reduction in pain and improving the mobility in osteoarthritis . As Glucosamine is unstable, therefore, mostly its salts either hydrochloride or sulfate are used in therapy. Our research group has been extensively investigating, for more than a decade, various types of drug delivery systems containing different model drugs, including but not limited to Ketoprofen [11,12]. In the present study we have explored the use of D-Glucosamine HCl as a hydrophilic carrier to enhance the solubility and dissolution rate of hydrophobic drug Ketoprofen Graph 1. Glucosamine HCl was used in this study because it is more stable than Glucosamine Sulfate .
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The melting or fusion method, first proposed by Sekiguchi and Obi involves the preparation of physical mixture of a drug and a water-soluble carrier and heating it directly until it melted. The melted mixture is then solidified rapidly in an ice bath under vigorous stirring. The final solid mass is crushed, pulverized and sieved. However many substances, either drugs or carriers, may decompose or evaporates during the fusion process which employs high temperature. Some of the means to overcome these problems could be heating the physical mixture in a sealed container or melting it under vacuum or in presence of inert gas like nitrogen to prevent oxidative degradation of drug or carrier. 20
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The hydrotropes are known to self-assemble in solution 98 .The classification of hydrotropes on the basis of molecular structure is difficult, since a wide variety of compounds have been reported to exhibit hydrotropic behaviour. Specific examples may include ethanol, aromatic alcohols like resorcinol, pyrogallol, catechol, a- and b-naphthols and salicylates, alkaloids like caffeine and nicotine, ionic surfactants like diacids, SDS (sodium dodecyl sulphate) and dodecylated oxidibenzene. 99 The aromatic hydrotropes with anionic head groups are mostly studied compounds. They are large in number because of isomerism and their effective hydrotrope action may be due to the availability of interactive pi- orbitals. Hydrotropes with cationic hydrophilic group are rare, e.g. salts of aromatic amines, such as procaine hydrochloride. Besides enhancing the solubilization of compounds in water, they are known to exhibit influences on surfactant aggregation leading to micelle formation, phase manifestation of multicomponent systems with reference to nanodispersions and conductance percolation, clouding of surfactants and polymers, etc. Other techniques that enhance the solubility of poorly water soluble drugs include salt formation, change in dielectric constant of solvent, Chemical modification of the drug, use of hydrates or solvates, use of Soluble prodrug, Application of ultrasonic waves, spherical crystallization. 100
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Novel nanosizing and solubilization technology whose application has increased particle size reduction via supercritical fluid (SCF) processes. A supercritical fluid (SF) can be defined as a dense non condensable fluid. Supercritical fluids are fluids whose temperature and pressure are greater than its critical temperature (Tc) and critical pressure (Tp). A SCF process allows micronization of drug particles within narrow range of particle size, often to sub-micron levels. Current SCF processes have demonstrated the ability to create nanoparticulate suspensions of particles 5 to 2,000 nm in diameter. The low solubility of poorly water-soluble drugs and surfactants in supercritical CO 2 and the high pressure
The higher percent released from the AMC containing glycerol is due to its high porosity causing higher influx of dissolution medium resulting in quick build-up of osmotic pressure inside the system. Osmogents had comparable and profoundly positive effect on drug release. It was found that drug release rate increases with the amount of osmogent due to increase in water uptake hence increased driving force for drug release. In-vitro release study showed that the F2 formulation showed higher drug release, this may be attributed by the additive effect of both of osmogents used. So, we can conclude that the AMC formulation approach could be used for both osmotic delivery and as controlled release formulation for poorly soluble drugs.
As a matter of fact, more than one-third of the drugs listed in the U.S. Pharmacopoeia fall into the poorly water-soluble or water-insoluble categories. It was reported a couple of decades ago that more than 41% of the failures in new drug development have been attributed to poor biopharmaceutical properties, including water insolubility, while it was still indicated recently that about 50% failure of drug candidates was due to poor “drug-like” properties. It is commonly recognized in the pharmaceutical industry that on average more than 40% of newly discovered drug candidates are poorly water-soluble. Poor “drug like” properties of lead compounds led to ineffective absorption from the site of administration, which has been designated as an important part of the high clinical failure due to poor pharmacokinetics. The basic aim of the further formulation & development section is to make that drug available at proper site of action within optimum dose.
Co-solvency is defined as a process in which the solubility of the drug is increased by addition of water miscible solvents. The added solvents are called as co- solvents.the solublization effect brought about is dependent on the polarity of drug, solvent and co- solvent. Examples of various co-solvents are propylene glycol, polyethylene glycol, ethanol etc. The co-solvents basically enhance the solubility in of the drug and reduce difference between polarity of the drug and water system thereby enhancing the solubility. The mechanism involved in solubility enhancement by co-solvency is reduction in interfacial tension between aqueous solution and hydrophobic solutes and reduces the contact angle between liquid and solid.