Co-Solvent Evaporation Method for Enhancement of Solubility and Dissolution Rate Of

“CO-SOLVENT EVAPORATION METHOD FOR ENHANCEMENT OF SOLUBILITY AND DISSOLUTION RATE OF ANTI-HYPERLIPIDEMIC DRUGS”

SYNOPSIS FOR

M.PHARM DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH

SCIENCES

KARNATAKA,BANGALORE

SUBMITTED BY

Ms. DIVYA.V

M.PHARM PART 1st YEAR

DEPARTMENT OF PHARMACEUTICS

UNDER THE GUIDANCE

Mrs. DIVYA.S.KUMAR

ASST.PROFESSOR

THE OXFORD COLLEGE OF PHARMACY

BANGALORE-68.

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

ANNEXURE – II

Proforma for Registration of Subject for Dissertation

6.0 BRIEF RESUME OF THE INTENDED WORK:

6.1 Need for the study

Hyperlipidemia is a condition where there is an elevation of lipids or fats in blood which is due to increase in triglycerides or cholesterol or both which can be treated by using anti-hyperlipidemic drugs1.

Class of drugs that include in anti-hyperlipedimic category are Statins which lowers cholesterol and Fibrates which takes control over triglycerides, mainly used in treatment of fatal cardiovascular abnormalities caused due to high cholesterol in blood2.

Statins(orHMG-CoA reductase inhibitors) are a class of drug used to lowercholesterollevels by inhibiting the enzymeHMG-CoA reductase, which plays a central role in the production of cholesterol in theliver. Increased cholesterol levels have been associated withcardiovascular diseasesand statins are therefore used in thepreventionof these diseases.

Statins act bycompetitively inhibitingHMG-CoA reductase, the first committedenzymeof theHMG-CoA reductase pathway as they are similar to HMG-CoA on a molecular level they take the place of HMG-CoA in the enzyme and reduce the rate of production ofmevalonate, the next molecule in thecascade that eventually produces cholesterol. This ultimately reduces cholesterol via several mechanisms3.

Classof drugs that are referred to as Statins include includes Lovastatin(Mevacor),Simvastatin(Zocor),Fluvastatin(Lescol),Atrovastatin, Paravastatin (Pravachol) etc..

A number of synthesized chemical molecules suffer from low aqueous solubility problems.Although these molecules have potential thermodynamic properties, they show low bioavailability due to poor aqueous solubility and these molecules became unsuccessful4.

Statins selected for the present work are poorly soluble drugs,hence their bioavailability is less making the drugs less effective for the therapy.So their solubility is enhanced by a new approach co-solvent evaporation technique for increasing their bioavailability.

6.2 Review of literature

Literature review for undertaking the study was done by referring to articles published in various National and International Journals, official standard books and referring to various websites on the internet.

1. A number of synthesized chemical molecules suffer from low aqueous solubility problems. Enhancement of aqueous solubility, dissolution rate, and bioavailability of drug is a very challenging task in drug development. In the present study, solubility and dissolution of poorly aqueous soluble drug Simvastatin (SIM) was enhanced using hydrophilic, low viscosity grade polymer hydroxypropylmethylcellulose (HPMC K3LV). The co-solvent evaporation method was developed for efficient encapsulation of hydrophobic drug in polymer micelles of HPMC K3LV. Spray drying and rota evaporation method were applied for solvent evaporation. Co-solvent-evaporated mixture in solid state was determined by differential scanning calorimetry (DSC), X-ray diffraction studies (XRD), scanningelectron microscopy, and Fourier-transform infrared spectroscopy. In vitro, in vivo studies were performed on co-solvent-evaporated mixture and compared with SIM. In vivo study was conducted on healthy albino rats (Wister strain), and formulations were administered by oral route. Results of the study show the conversion of crystalline form of SIM into amorphous form. The dissolution rate was remarkably increased in co-solvent-evaporated mixtures compared to SIM. Co-solvent evaporated mixtures showed better reduction in total cholesterol and triglyceride levels than the SIM. The low viscosity grade HPMC acts as a surfactant, which enhances the wetting of drug and thus improves the solubility of drug. The co-solvent evaporation method provides good encapsulation efficiency and produces amorphous form of SIM, which gave better solubility and dissolution than the crystalline SIM4.

1. Role of various hydrophilic binders for enhancement of dissolution of a poorly soluble drug, Raloxifene Hydrochloride (RLX-HCl), using solid oral dosage form. Solubility study for pure drug was done in different relevant media, which results in poor solubility of drugs. Hydrophilic binders viaPolyvinyl pyrrolidone, Hydroxy propyl methyl Cellulose, Hydroxy propyl cellulose were investigated for the purpose to improve the solubility in the formulation. Comparison was made with hydrophobic binder viaEthyl cellulose. Dissolution behaviour of different formulation and pure drug was studied in different relevant media, which reveals significant improvement in dissolution behaviour of drug was observed using hydrophilic binder5.

1. Piroxicam is a Non‐steroidal anti inflammatory, analgesic and anti‐pyretic drug which is widely used in Muscle‐skeletal disorder like osteoarthritis. Piroxicam has bad taste, half life of 30 hrs and poor water solubility. So the present work was focused on prepare the microspheres to improve solubility and dissolution of Piroxicam using two grade of chitosan with different drug: polymer ratio by spray‐drying technique. The effect of different polymers and drug–polymer ratios on solubility and dissolution of microspheres was investigated. The prepared microspheres were characterized by Fourier transform infrared spectroscopy, Differential scanning colorimetric, XRD study and scanning electron microscopy, Drug loading and drug‐release properties. Spray dried microspheres of exhibited decreased crystallinity. The solubility and dissolution of the Spray dried microspheres of both the polymers with different ratio were improved compared with pure sample of piroxicam. Hence this spray drying technique can be used for formulation of tablets of piroxicam by direct compression with directly compressible tablet excipients6.

1. Fenofibrate is a lipid lowering drug used in the treatment of hyperlipidemia, which is not soluble in water and lower absorption in gastric fluid. In order to improve the solubility and oral absorption of the drug in gastric fluid and to enhance its dissolution rate solid dispersions and Lyophilisation of dispersion is designed and evaluated. Solid dispersions of Fenofibrate were prepared using PEG 6000, Poloxamer 407 and a mixture of PEG 6000 and Poloxamer 407(1:1 mixture). The effect of melt and solvent methods of preparation of solid dispersion on dissolutionbehaviour was also investigated. Dissolution studies indicated a significant increase in dissolution of Fenofibrate when dispersed in PEG6000 and Poloxamer 407. Physical mixtures containing PEG and Poloxamer 407 also showed improved dissolution of Fenofibrate as compared with that of pure drug, indicating the solubilising effect of PEG6000 and Poloxamer 407. Solid dispersions containing Fenofibrate /Poloxamer 407, 1: 8, showed a 14-fold increase in dissolution after 60 min (D60) and another dispersion containing Fenofibrate /PEG 6000, 1:10, showed an 8-fold increase in the 0.1 N HCl systems. The dispersion containing six parts of the PEG 6000: Poloxamer 407 mixture (PEG 4000/PEG 6000, 1:1 mixture) showed a 12-fold increase in D60 as compared with pure drug. When multi-carrier solid dispersion containing six parts of mixture was prepared by the solvent method, the D60 value was about 2-fold that of the same dispersion prepared by the melt method. The dissolution of lyophilized solid dispersions further increased the dissolution of Fenofibrate significantly7.

1. Most of the new chemical entities coming out from High-throughput screening in drug discovery process are failing due to their poor solubility in the water. Poorly water-soluble drugs show many problems in formulating them in conventional dosage forms. One of the critical problems associated with poorly soluble drugs is too low bioavailability. The problem is even more complex for drugs belonging to BCS CLASS II category, as they are poorly soluble in both aqueous and organic media, and for those drugs having a log P value of 2. There are number of formulation approaches to resolve the problems of low solubility and low bioavailability. These techniques for solubility enhancement have some limitations and hence have limited utility in solubility enhancement. Nanotechnology can be used to resolve the problems associated with these conventional approaches for solubility and bioavailability enhancement. Nanotechnology is defined as the science and engineering carried out in the nanoscale that is 10-9 meters. The present article describes the details about nanosuspensions. Nanosuspensions consist of the pure poorly water-soluble drug without any matrix material suspended in dispersion. The review article includes the methods of preparation with their advantages and disadvantages, characterization and evaluation parameters and pharmaceutical applications. A nanosuspension not only solves the problems of poor solubility and bioavailability but also alters the pharmacokinetics of drug and thus improves drug safety and efficacy8.

1. Melt granulation technique to improve the solubility and dissolution characteristics of a poorly water-soluble drug, Rifampicin. Melt granulation technique is a process by which pharmaceutical powders are efficiently agglomerated by a meltable polymers and surfactants. The advantage of this technique compared to a conventional granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation. Granules were prepared by using polymer like different grades of polyethylene glycol and surfactant like different grades of poloxomers. The granules were characterized using powder XRD, DSC and FTIR techniques. A significant enhancement in the in vitro dissolution profiles of the melt granules was observed compared to the pure drug and drug excipient physical mixtures. Besides the remarkable enhancement of drug dissolution rate of the granulates in comparison to physical mixtures and pure drug, no significant differences were found between the dissolution profiles of the melted granulates containing lactose or crospovidone. XRD data confirmed crystalline drug in the melted granules. DSC results indicated change in internal energy of Rifampicin with polymers and surfactant in the melted granulated. In conclusion, the results of this work suggest that melt granulation is a useful technique to enhance the solubility and dissolution rate of poorly water-soluble drugs, such as, Rifampicin9.

1. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown.Drug efficacy can be severely limited by poor aqueous solubility and some drugs also show side effects due to their poor solubility. There are many techniques which are used to enhance the aqueous solubility. The ability to increase aqueous solubility can thus be a valuable aid to increasing efficiency and/or reducing side effects for certain drugs. This is true for parenterally, topically and orally administered solutions. Hydrotropy is one of the solubility enhancement techniques which enhance solubility to many folds with use of hydrotropes like sodium benzoate, sodium citrate, urea, niacin amide etc. and have many advantages like; itdoesnotrequirechemicalmodification ofhydrophobic drugs,use of organic solvents, or preparation of emulsion system10.

1. There was a great interest in solid dispersion systems during the past four decades to increase dissolution rate and bioavailability of poorly water-soluble drugs, their commercial use has been very limited, primarily because of manufacturing difficulties and stability problems. Solid dispersions of drugs were generally produced by melt or solvent evaporation methods. The materials, which were usually semisolid and waxy in nature, were hardened by cooling to very low temperatures. They were then pulverized, sieved, mixed with relatively large amounts of excipients. Here we tried the improving the solubility of Valdecoxib by using different carriers and solid dispersion techniques. Solid dispersions demonstrated a higher dissolution rate than pure drug. The Valdecoxib: PEG 6000 shows highest dissolution rate than the other formulations. Hence, the solid dispersion technique with PEG 6000 provides a promising way to increase the solubility and dissolution rate of poorly soluble drugs11.

1. To increase the solubility, and dissolution rate of Rosuvastatin Calcium (RST), a poorly water-soluble 3-hydroxy3-methyl glut aryl CoA (HMG-CoA) Reductase inhibitor through inclusion complexation with β cyclodextrin (β-CD).The phase solubility profile indicated that the solubility of RosuvastatinCa was significantly increased in the presence of β-CD and Apparent stability constant (KC) was found to be 42.003M-1. The inclusion complexes were prepared by three different methods viz. physical, kneading, Co-evaporation and precipitation method. The prepared complexes were characterized using FTIR, Differential scanning Calorimetry and Powder X-ray diffractometry. The inclusion complex prepared with β-CD by kneading method exhibited greatest enhancement in solubility and fastest dissolution (98.96% RST release in 30 min) of RST. The inclusion complex containing RST: β-CD (1:1) was formulated into tablets using superdisintegrants like sodium starch glycolate, Crosspovidone and Crosscarmellose. The prepared tablet were evaluated for various post compression parameters like hardness, friability, weight variation, thickness, drug content and in-vitro dissolution. The stability of tablets was studied and no significant changes were detected in the dissolution profile of tablets after 1 month12.

1. Solubility, it is the phenomenon of dissolution of solid in liquid phase to give a homogenous system and is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response. Poorly water-soluble drugs after oral administration often require high doses in order to reach therapeutic plasma concentrations. The bioavailability of an orally administered drug depends on its solubility in aqueous media over different pH ranges. The insufficient dissolution rate of the drug is the limiting factor in the oral bioavailability of poorly water soluble compounds. Various techniques are used for the improvement of the aqueous solubility, dissolution rate, and bioavailability of poorly water soluble drugs include micronization, chemical modification, pH adjustment, solid dispersion, complication, co‐solvency, micellar solubilisation, hydrotropy etc. The purpose of this review article is to describe the techniques of solubilisation for the attainment of effective absorption with improved bioavailability13.

1. Among all newly discovered chemical entities about 40% drugs are lipophillic and fail to reach market due to their poor water solubility. The solubility behaviour of drugs remains one of the most challenging aspects in formulation development. Solid dispersions have tremendous potential for improving drug solubility. The present review is devoted to production of solid dispersions, various carriers used and the advantageous properties of solid dispersion14.

1. Celecoxib has very low water solubility. It forms a complex with β-cyclodextrin (βCD) both in aqueous and in solid state. It was observed that due to formation of the inclusion complex, the solubility and dissolution rate of Celecoxib were enhanced. The formation of 1:1 complex with βCD in solution was confirmed by phase solubility and spectral shift studies. The apparent stability constants calculated by these techniques were 881.5 and 341.5 M−1, respectively. The solid inclusion complexes of Celecoxib and βCD were prepared by the kneading method using different molar proportions of βCD, and formation of solid inclusion complexes of Celecoxib and βCD at different molar ratios were confirmed by differential scanning calorimetry. Enhancement of dissolution rates with increasing quantity of βCD in the complex was observed. It was also observed that the complexes exhibit higher dissolution rates than the pure drug and physical mixture15.

6.3 Objectives of the study

In the present, work attempt will be made to

Design formulations of the Anti-hyperlipidemic drug to form inclusion complex,by performing co-solvent evaporation technique for the drug selected with an aim to increase solubility and dissolution rate of the drug.

Optimization techniques will be used to prepare atleast six such desirable formulations,using the drug and other related excipients.

Compressing the tablets by using the co-solvent evaporated product.

To evaluate the tablets containing Anti-hyperlipidemic drug.

Short term Stability studies.

To perform bioequivalence studies with the prepared formulation and marketed product.

7.0 Materials and Methods

The suitable drug sample for this proposal modelAnti-hyperlipidemics are Simavastatin,Atrovastatin,Rosuvastatin, Pravastatin, Lovastatin, Fluvastatin.

The materials will be choosen after compatibility; studies with the active ingredient were performed.

Method : Co-solvent evaporation method,Wet granulation technique, Direct compression technique.

7.1 Source of data:

Review of literature was obtained from the library of The Oxford College of pharmacy, from World Wide Web, International Journal of Pharmaceutical Sciences, Journal of Chemical and Pharmaceutical Research, American Pharmaceutical Review, J-gate@Helinet of RGHUS, Science Direct, Pub med, European Journal OF Pharmaceutical Sciences, Library of Rajiv Gandhi University of Health Sciences.

7.2Method of collection of data:

Co-Solvent Evaporation Method

The solvent evaporation of drug and polymer solution in different ratio will be carried out by using Buchi Rota evaporator (Hidolf- Germany). The dried rota evaporated mixture of drug with polymer and drug is denoted as final formulation. This blend of mixture, will be compressed into tablets after adding the required additives.

The mixed blend will be subjected to Preformulation studies.

Studies to be determined for co-solvent evaporated mixture in solid state:

 Solubility Study.

 Differential Scanning Calorimetry.

 Powder X-Ray Diffraction Studies.

 Scanning Electron Microscopy.

 Fourier-Transform Infrared Spectroscopy.

 Bulk density.

 Tap density.

 True density.