• Improvement of oral bioavailability and reduction in intersubject/intrasubject variability- Micro or Nano emulsified oil droplets provide drug in dissolved form, increase in specific surface area for absorption, enable more efficient drug transport through intestinal aqueous boundary layer, increase the extent of its transportation via intestinal lymphatic system and avoid pre-systemic first pass effect leading to improved bioavailability and reduction in intersubject/intrasubject variability of severely poorlywatersoluble drugs.
ABSTRACT: Objective: The prodigious challenge in the pharmaceutical industries was to enhance the solubility and the permeability of those drugs as key factors to improve their bioavailability. Various techniques have been used to improve the drug water solubility and release profile, and solid dispersions are considered to be the most successful techniques. The aim of the present study was to improve the solubility and bioavailability of a poorlywater- soluble antihypertensive drug (Eprosartan) in the human body, using a solid dispersion technique (hot melt extrusion) and comparison with other methods. Methods: The development of solid dispersions as a practically viable method to enhance the bioavailability of poorlywater-soluble drugs to overcome the limitations of previous approaches such as salt formation, solubilization by co-solvents and particle size reduction studies revealed that drugs in solid dispersion need not necessarily exist in the micronized state. Solid solution was prepared by solvent evaporation, fusion method, hot melt extrusion technique at 1:1.1, 1:2 (Eprosartan: Soluplus) and 1:1.5:0.5 (Eprosartan:Soluplus: Kollidan/Plasdone) ratios respectively. Solid Solution was evaluated for saturation solubility, dissolution rate, XRD, FTIR, and DSC. Results: From the studies, it was concluded that the solubility of Eprosartan was increased by the solid dispersion approach. Among the three techniques, the solubility of the drug increased by hot melt extrusion technique when compared to solvent evaporation and fusion methods. Therefore, the carrier surplus was suitable for enhancement of solubility of Eprosartan than other carriers used in this investigation such as kollidon VA64 and plasdone K29/32 and DSC, XRD data concluded that hot melt extrusion process devastates the edge peaks of Eprosartan which
Atovaquone and Satrinidazole have poor solubility resulting in low oral absorption hence low oral bioavailability. Hence to improve the solubility of poorly Atovaquone and Satrinidazole, hydrophilic polymers were used to enhance the dissolution by solid dispersion technique. Polyethylene Glycol 4000 and PVP k30 used to enhance the dissolution of both the drug by Solubilisation. Many alternative techniques have been used to improve such bioavailability; this study thus employed the simple solid dispersion technique and incorporated excipients which can increase the bioavailability of these drugs directly enhancing the dissolution rate of the drug and indirectly by reducing particle size. The aim of present work is to enhance the dissolution of poorlywatersoluble drug by using solid dispersion technique. To improve the dissolution rate, by using the various concentration of carrier or matrix with drug and hence, improve the bioavailability of poorlywatersoluble drug by formulating solid dispersion. To enhance the solubility of poorlywatersoluble drug, by means of solubilising agent. In case of poorlywatersoluble drug, dissolution may be the rate limiting step in the process of absorption. In such case, we can improve their solubility and dissolution rate. To study the effect of surfactant on the solid dispersion of poorlywatersoluble drug.
The work on the influence of modified gum karaya (MGK) on the oral bioavailability of a poorlywater- soluble drug, nimodipine (NM), in comparison with that of gum karaya (GK) was carried out. A cogrinding method was selected to prepare mixtures of NM and GK or MGK in a 1:9 ratio (NM:GK/MGK). Differential scanning calorimetry (DSC), Fourier transmission infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), solubility studies, and in vitro release studies were per- formed to characterize the properties of the cogrinding mixtures. No drug-carrier interactions were found, as confirmed by DSC and FT-IR studies. The XRD study revealed that the crystallinity of NM was identical in both the cogrinding mixtures and was decreased when compared to that of physi-cal mixtures or pure NM. 32 Further work on enhancement of in vitro dissolution of poorlysoluble drug glimepiride by preparing solid dispersions using modified gum karaya was carriedout. Low viscosity with comparable swelling characteristics as compared to GK of modified form of gum karaya may lead to improvement in dissolution behavior of solid dispersion batches. Also, the conversion of crystalline form of drug to amorphous form may be a responsible factor, which was further confirmed by DSC, FTIR studies, and X-RD studies. 38
assembled, nanosized colloidal particles with a hydrophobic core and hydrophilic shell 55 . The specialized structure makes micelles suitable carrier for poorlywatersoluble drugs that account for approximately 25% of conventional, commercially available therapeutics and nearly 50%of candidates identified through screening techniques 56-57 . Insoluble drugs often are characterized by poor bioavailability and rapid clearance after administration, characteristics that are associated with low therapeutic efficacy and high toxicity 58 . Thus using amphiphilic, solubilizing agents, Cremophor EL, can increase water solubility. However a number of problems associated with its use were overcome by developing poly (N- vinylpyrrolidone) - block- poly (D, L- lactide) copolymer that formed polymeric micelles in water and solubilized anticancer drugs 59 (paclitexal, docetaxel, teniposide and etoposide).
The progress in treatment of diseases has been evident with the upsurge in development of new drugs. An estimated 40% of these drugs are poorlywatersoluble. The enhancement of oral bioavailability of such poorlywatersoluble drugs remains one of the most challenging aspects of drug development. The development of Liquisolid Compact Technology as a practically viable method to enhance bioavailability of poorlywater- soluble drugs overcome the limitations of previous approaches such as salt formation, solubilisation by co solvents, and particle size reduction and other methods. Much of the research that has been reported on Liquisolid Compact technologies involves drugs that are poorlywater-soluble and highly permeable to biological membranes as with these drugs dissolution is the rate limiting step to absorption. Liquisolid Compact technologies are particularly promising for improving the oral absorption and bioavailability of BCS Class II drugs 1 . The Bio pharmaceutics Classification System (BCS) 2 . According to the BCS, drugs are classified as follows:
The biotransformation o f nitriles is o f interest because a number o f economically important organic compounds are currently produced from nitrile starting materials (Jallageas et al., 1980). A biological method o f production offers a greener, more selective process and in one case, that of acrylamide production, the yield and purity is better than the original chemical method (Yamada and Kobayashi, 1996). Nitrile hydratase (NHase) is the enzyme of greatest interest for the hydrolysis of nitriles to amides. Consequently over the past decade several processes have been developed for the production o f commodity chemicals including acrylamide and nicotinamide and for the treatment o f waste (Yamada and Kobayashi, 1996; Kobayashi and Shimizu, 1998). The most significant to date is the Nitto process which utilises NHase for the production of acrylamide, one of the most important commodity chemicals (Yamada and Kobayashi, 1996). NHase catalysed production of acrylamide currently yields 30,000 tonnes of product per annum. The application o f NHase for the production of acrylamide removed the use of a toxic copper catalyst in the Nitto process and simplified the process due to a reduction in the number o f reaction steps and waste material. Due to the success o f the Nitto process NHase is of intense scientific interest both for its application in process biotransformations and its novel biochemistry (Kobayashi and Shimizu, 2000; Endo et a l, 2001). Currently the process options for the biotransformation o f poorlywatersoluble nitriles have not been thoroughly investigated.
In recent years, the formulation of poorlysoluble compounds presented interesting challenges for formulation scientists in the pharmaceutical industry. Up to 40% of new chemical entities discovered by the pharmaceutical industry are poorlysoluble or lipophilic compounds, which lead to poor oral bioavailability The enhancement of oral bioavailability of poorlywatersoluble drugs remains one of the most challenging aspects of drug development. Atorvastatin (ATR) is a synthetic lipid-lowering agent. 1-3 Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. According to the biopharmaceutical classification, ATR comes under Class II (low solubility and high permeability). Because of the limited aqueous
enhancement oral bioavailability of poorlywater-soluble drugs represent an actual challenge for pharmaceutical research, with the aims of improving drug therapeutic effectiveness as well as creating new market opportunities. The BCS class II drugs are water-insoluble (solubility equal or less than 100 µg of solute per 1 ml of solvent) but have high membrane permeability is only limited by dissolution. The energy-driven step is dissolution of crystalline solid in a process. In general, the kinetics of the process depends on solute, solvent chemical nature, microstructure and on the
Low solubility compounds show dissolution rate limited absorption and hence poor absorption, distribution and target organ delivery. Improvement of aqueous solubility in such a case is valuable goal to improve therapeutic efficacy. Complexation with CDs by different methods like physical mixing, melting, kneding, spray drying, freeze drying, co-evaporation has been reported to enhance the solubility, dissolution rate and bioavability of poorlywatersoluble drugs. The formation of inclusion complex can be confirmed by DSC, FTIR, XRD and SEM study. This review aims to assess the use of cyclodextrines as complexing agents to enhance the solubility of poorlysoluble drugs and hence to resolve the many issues associated with developing and commercializing poorlywatersoluble drugs.
Finally, the question comes to the mind that whether the application of solid dispersion technology can be considered as a universal approach for enhancing the solubility of poorlywater-soluble compounds. Currently, not any of the strategies used for increasing the solubility of drug in aqueous media is appropriate for all drugs and dosing requirements. However, determining the stability of the amorphous state of solid dispersions remains an area of interest, which seeks the attention of researchers and there is still more to be worked upon to get the extreme benefit of this effective technique. But among all the techniques used in the industries to enhance dissolution of poorlywatersoluble drug, solid dispersion emerge to be the most versatile and is applicable to majority of compounds and their dosing requirements.
arthritis, osteorthritis and other musculoskeletal disorder. Ibuprofen primarily absorbed from lower part of gastrointestinal tract. The main objective of the study was to develop, evaluate and optimization of tablets containing poorlywatersoluble drug by moisture activated dry granulation method, thereby reducing the production cost of tablet.
Improving oral bioavailability of drugs those given as solid dosage forms remains a challenge for the formulation scientists due to solubility problems. Over the years a variety of solubilization techniques have been studied and widely used, as maximum drugs are poorlywatersoluble in pharmaceutical field. The enhancement of dissolution rate and oral bioavailability is one of the greatest challenges in the development of poorlywatersoluble drugs. Solid dispersions have attracted many researchers as an efficient means of improving the dissolution rate and hence the bioavailability of a range of poorlywater-soluble drugs. The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic inert carrier or matrix and a hydrophobic drug. Solid dispersion can form either a eutectic mixture or solid solution or glass solution or amorphous precipitation in a crystalline carrier or compound or complex formation. The focus of this review article is on the advantages, limitations, various methods of preparation and characterization of the solid dispersion.
The term ‘Hydrotropy’ was put forward by Carl Neuberg 1 to describe increase in solubility of a solute by the addition of fairly high concentrations of alkali metal salts of various organic acids. Hydrotropy enhances solubility of drug by many folds with use of hydrotropes like sodium benzoate, sodium citrate, urea, niacinamide etc. and have many advantages like; it does not require chemical modification of hydrophobic drugs, use of organic solvents, or preparation of emulsion system etc 2 . Hydrotropic agents are also a type of solubilizers which increase the solubility of poorlywatersoluble drugs 3 . Examples of various hydrotropic agents that are used as excipients in order to increase aqueous solubility of drug are urea, nicotinamide, sodium benzoate, sodium salicylate, sodium acetate, piperazine, nicotinamide, sodium toluate 4 - 13 .
Atorvastatin Calcium used to lower cholesterol level in plasma of body by competitive inhibiting HMG-CoA reductase, the rate determining enzyme in cholesterol biosynthesis via the mevalonate pathway. However its effectiveness is limited by its poor water solubility and very low oral bioavailability. Therefore the aim of present investigation was to develop an optimal lipid based formulation for advanced delivery of poorlywatersoluble drug Atorvastatin Calcium, for enhancing its aqueous solubility and oral bioavailability. Oil and surfactants were screened based on drug solubility. Pseudo-ternary phase diagrams were constructed to determine suitable surfactant to cosurfactant ratio for the development of lipid based formulation as SMEDDS. Atorvastatin calcium loaded SMEDDS was developed and characterized. Solidification of SMEDDS was done by spray drying technique using aerosil 200 as solid carrier. The drug release study shows that the release of Atorvastatin will enhances in SMEDDS formulation as compared to plain drug.
Currently more than 50% of compounds identified are water insoluble and or poorlywatersoluble. These molecules are difficult to formulate using conventional approaches (for their poor aqueous solubility) and are associated with numerous formulation-related performance issues. Formulating these compounds using lipid based systems is one of the growing interest and suitable drug delivery strategies are applied to this class of molecules. The rapid growth and investment in the use of lipid based systems in product development is primarily due to the diversity and versatility of pharmaceutical grade lipid excipients and drug formulations and their compatibility with liquid, semi-solid and solid dosage forms. Lipid formulations such as self-emulsifying/ microemulsifying/ nanoemulsifying drug delivery systems have been attempted in many researches to improve the BA and dissolution rate for their better dispersion properties. One of the greatest advantages of incorporating the poorlysoluble drug into such formulation products is their spontaneous emulsion and or micro emulsion/ nanoemulsion formation in aqueous media. The performance and ongoing advances in manufacturing technologies has rapidly introduced lipid-based drug formulations as commercial products into the marketplace with several others in clinical development. The goal of the current review is to present the characteristics feature, development and utilization of oral lipid based formulations within drug delivery region. The review also aims to provide an insight of the in vitro evaluation of lipid based systems and their potential limitations.
their ability to moleculerly encapsulate a wide variety of drugs into their hydrophobic cavity which imparts changes in physicochemical properties, resulting in the enhancement of water solubility and drug-dissolution rate. Poorlywatersoluble drugs usually show low bioavailability as their absorption rate is dissolution-rate limited and is consquently low. Cyclodextrins are considered to be good candidates for dissolution-rate enhancement of drugs having poor water solubility. (Hedges R.A et.al). Although CDs can increase the aqueous solubility of drugs, many applications need large amount of CDs. But for several reasons, such as production cost and toxicity, CD amount have to reduced in pharmaceutical use. To achieve this goal, several approaches can be considered. The first is the use of CDs, which present a higher solubility in water. The second method consists in adding a water-soluble polymer, like PVP, and HPMC, with the aim to increase the aqueous solubility of both the complex and the drug itself. Cyclodextrins (sometimes called cycloamyloses) are a family of compounds made up of sugar molecules bound together in a ring (cyclic oligosaccharides). Cyclodextrins are produced from starch by means of enzymatic conversion. They are used in food, pharmaceutical, and chemical industries, as well as agriculture and environmental engineering.
BCS class II drugs offer challenging problems in their pharmaceutical product development process because of their low solubility and dissolution rates. The basic drug will precipitate upon a shift from gastric pH (pH 1.5) to intestinal pH (pH 6.5-7.0). With the increasing number of poorlywater-soluble compounds in present day drug discovery pipelines, the concept of supersaturation as an effective formulation approach for enhancing bioavailability is gaining steam. This is intended to design the formulation which yields significantly high intraluminal concentrations of the drug than the thermodynamic equilibrium solubility through achieving supersaturation and therefore to enhance the intestinal absorption. The major challenges faced by scientists in developing supersaturatable formulations include controlling the rate and degree of supersaturation with the application of polymeric precipitation inhibitor and maintenance of post-administration supersaturation. The extent of precipitation can be measured using various techniques. The precipitation of a poorlywater-soluble weakly basic drugs were investigated under different concentration. It has been shown that the drug precipitates rapidly under supersaturation. Solid dispersion techniques and self-micro-emulsifying drug delivery systems (SMEDDS) with the inclusion of certain polymers can prevent recrystallization, stabilize amorphous APIs, enhance solubility and process ability and facilitate dissolution. Different polymers have been evaluated as precipitation inhibitors. HPMC was shown to be the most potent polymeric precipitation inhibitor.
www.wjpr.net Vol 7, Issue 9, 2018. 960 clinically relevant dose reduction.  Solid dispersion is a useful method to disperse drugs in a carrier matrix. The interaction between the drug and carrier is responsible for drug dispersion, and may depress the crystallisation of drug in the prepared system. Solid dispersions are prepared mainly by a melting method or a solvent method, which are usually consisted of two components, a poorlywatersoluble drug and a watersoluble polymer like polyvinyl pyrrolidone, polyethylene glycol, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, micro crystalline cellulose, and so on.  Rosuvastatin is a crystalline, poorlywater- soluble drug and therapeutically HMG-CoA Reductase inhibitor. The main aim of the present study was to increase dissolution rate of Rosuvastatin by increase the aqueous solubility Rosuvastatin. Solid dispersion is the techniquechosen to increase the solubility of Rosuvastatin by using solvent evaporation by using different carriers like microcrystalline cellulose, Urea, Croscormellose sodium, Crosspovidone. Solvent evaporation is most easy and convenient method for the preparation of solid dispersions. In this method, it contains a poorlywatersoluble drug, watersoluble carrier and an organic solvent like methanol, ethanol, pronolol etc.
It can be concluded that the concept of hydrotropic solubilization technique is novel, safe, eco-friendly and economic for enhancing bioavailability of poorlywater-soluble drugs. Here, miraculous enhancement in solubility of Valsartan was observed in hydrotropic solution of piperazine anhydrous that marked its importance in pharmaceutical field where solubility of poorlywatersoluble drugs has been a critical step in production of dosage forms.