“A STUDY TO IMPROVE THE SOLUBILITY OF POORLY SOLUBLE DRUGS BY USING SUITABLE PHARMACEUTICAL TECHNIQUES”

DISSERTATION PROTOCOL

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCESBANGALORE, KARNATAKA.

BY

MOSALI SINDHU REDDY

M.PHARM, PART-IDEPARTMENT OF PHARMACEUTICS

T.JOHN COLLEGE OF PHARMACYGOTTIGERE, BANNERGATTA ROAD.

BANGALORE-83

UNDER THE GUIDANCE OF

Dr. SANDHYA K V, DEPARTMENT OF PHARMACEUTICS,

T.JOHN COLLEGE OF PHARMACY,GOTTIGERE, BANNERGATTA ROAD,

BANGALORE-83.

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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,BANGALORE, KARNATAKA.

ANNEXURER-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. NAME OF THE CANDIDATEAND ADDRESS (IN BLOCK LETTERS)

MOSALI SINDHU REDDY

T.JOHN COLLEGE OF PHARMACY, GOTTIGERE, BANNERGHATTA ROAD,BANGALORE-83, KARNATAKA.

2. NAME OF THE INSTITUTION T.JOHN COLLEGE OF PHARMACY, GOTTIGERE,BANNERGHATTA ROAD,BANGALORE-83, KARNATAKA.

3. COURSE OF STUDY AND SUBJECT

MASTER OF PHARMACY IN PHARMACEUTICS

4. DATE OF ADMISSION OF COURSE

06-07-2011

5. TITLE OF TOPIC

“A STUDY TO IMPROVE THE

SOLUBILITY OF POORLY SOLUBLE

DRUGS BY USING SUITABLE

PHARMACEUTICAL TECHNIQUES”

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6. SIGNATURE OF THE

CADIDATE(Mosali Sindhu Reddy)

7. REMARKS OF THE GUIDERECOMMENDED FOR THE DISSERTATION

WORK

8.NAME AND DESIGNATION

(in block letters)

8.1 GUIDE

8.2 SIGNATURE

SANDHYA KV, M. Pharm, Ph.D.DEPARTMENT OF PHARMACEUTICS

T.JOHN COLLEGE OF PHARMACY.

(Sandhya KV, M. Pharm, Ph.D.)

8.3 HEAD OF THE

DEPARTMENT

8.4 SIGNATURE

SANDHYA KV, M. Pharm, Ph.D.DEPARTMENT OF PHARMACEUTICS

T.JOHN COLLEGE OF PHARMACY.

(Sandhya KV M, Pharm, Ph.D.)

9.9.1 REMARKS OF

PRINCIPAL

9.2 SIGNATURE

FORWARDED AND RECOMMENDED FOR FAVOURABLE CONSIDERATION.

( Dr.Vineeth Chandy)

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10. BRIEF RESUME OF THE INTENDED WORK:

10.1 NEED FOR THE STUDY:

Oral ingestion is the most convenient and commonly employed route of drug delivery

due to its ease of administration, high patient compliance, cost-effectiveness, least sterility

constraints and flexibility in the design of dosage form. The preferred oral route of

administration is limited to those drug molecules that are permeable across the gastric mucosa

and are at least sparingly soluble. An increasing number of newly developed drug candidates

present poor water-solubility, which is the rate-limiting step to absorption of drugs from the

gastrointestinal tract. Approaches to overcome this factor are of great importance in drug

formulation Together with membrane permeability, the solubility/dissolution behavior of a drug

is a key determinant to its oral bioavailability. At present about 40% of the drugs being in the

development pipelines are poorly soluble, even up to 60% of compounds coming directly from

synthesis are poorly soluble.

The solubility of a solute is the maximum quantity of solute that can dissolve in

certain quantity of solvent or quantity of solution at a specified temperature.

Definition Parts of solvent required for one part of solute

Very soluble < 1Freely soluble 1 – 10Soluble 10 – 30Sparingly soluble 30 – 100Slightly soluble 100 – 1000Very slightly soluble 1000 - 10,000Insoluble > 10,000

Various formulation techniques are applied to compensate for their insolubility, slow dissolution

rate and consequently poor therapeutic efficacy. These include formulation of the amorphous

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solid form, nanoparticles, microemulsions, solid dispersions; melt extrusion, salt formation and

formation of water soluble complexes.

The Biopharmaceutics Classification System (BCS) is a scientific framework for

classifying a drug substance based on its aqueous solubility and intestinal

permeability. The BCS takes into account three major factors namely

solubility, intestinal permeability, and dissolution rate, all of which govern

the rate and extent of oral drug absorption. It classifies drugs into four

classes. Class II consists of water-insoluble drugs which, when dissolved, are well absorbed

from the gastrointestinal tract.

In this present study we would be working on drugs belonging to class II of BCS classification.

The dissolution rate is usually the rate-limiting step in drug absorption. Commonly drugs in this

class have variable absorptions due to the numerous formulation effects and in vivo variables

that can affect the dissolution profile. Thus the need to improve the solubility of drugs by using

various formulation strategies like nanoparticles, microemulsions, solid dispersions; melt

extrusion, salt formation and formation of water soluble complexes to enhance their

bioavailability, without changing the intrinsic ability of the drug molecules to permeate

biomembranes.[1]

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10.2 REVIEW OF LITERATURE :

Extensive literature review was made by referring various National and International

Journals, various databases and other web resources along with general books for pharmaceutical

scientists.

DANDAGI PM et al (2011), worked on nanocrystallization in enhancing dissolution property of

poorly soluble drugs such as griseofulvin by emulsion solvent diffusion method using acetone

and ethanol as solvents for drug. The formulations made of acetone were of smaller size and

possessed better dissolution velocity compared to ethanol, thus concluding that formulating

poorly water soluble drugs in the form of nanocrystallization would be a promising approach in

delivery of class II drugs by oral route in much efficacious way to enhance their bioavailability[1].

MUKHERJEE S et al (2012), reviewed on solubility enhancement techniques for the

improvement of effective absorption and bioavailability [2].

SHUKLA M et al (2010), worked on the effect of solubility of glipizide by using different

solubilization techniques such as solid dispersion, hydrotropy and micellar solubilization. The

drug glipizide showed improvement in solubility which was found to decrease in order of

hydrotropic solubilization > solid dispersion technique > micellar solubilization, concluding

that the best solubility results were obtained from hydrotropic solubilization method[3].

VARSHNEY S et al (2012), reviewed on employing different methods for solubility

enhancement of norflaxacin including solid dispersions, complexation (in presence of acidic

solubilizing additives; by EDTA and sodium caprate; and metal ion interaction), hydrotropic

solubilization, crystal modification resulting in improved dissolution and bioavailability of drug

leading to better therapeutic profile of drug[4].

BANSAL K et al (2011), worked on micronization technique for improving the dissolution of

Norethindrone where particle size reduction was achieved by air jet milling resulting in

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micronized Norethindrone showing higher dissolution rate. This suggests that micronization

technique can be used for the preparation of rapidly dissolving formulations of Norethindrone,

and could potentially lead to improvement in the in-vivo bioavailability of oral Norethindrone

Tablets[5].

GRACE FX et al (2012), worked on comparing the solubilising efficiency of five different

surfactants represented by Sodium Lauryl Sulphate, Tween 80,Polyethylene Glycol 6000,

Cremophor RH40, Poloxamer 407 on class II (low solubility, high permeability) antidiabetic

drugs such as Pioglitazone Hydrochloride and Glimepiride used in the treatment of type II

Diabetes mellitus (NIDDM) resulting that among the five surfactants used, Poloxamer 407

showed better dissolution and resulted in a stable dosage form[6].

HARTI JE, et al (2012), worked on to increase the apparent water solubility of josamycin, an

antibiotic belonging to the family of macrolide, by inclusion complexation with γ- cyclodextrin

(γ-CD). The phase-solubility profile and the stability constant of the complex showed an

improvement of the aqueous solubility of Josamycin propionate[7].

NAYAK AK et al (2012), worked on comparing the cosolvency using three different

cosolvents, namely PEG 400, PG, and glycerin on the aqueous solubility enhancement of a

poorly aqueous soluble drug etoricoxib. The less-polar solvents were found to increase the

aqueous solubility by greater extent, thus accentuating hydrophobic interaction mechanism and

among the various solvent-cosolvent blends investigated, water-PEG 400 was an acceptable

cosolvent in terms of side-effect profile and most efficient solubilizing cosolvent useful in the

development of liquid dosage forms containing etoricoxib[8].

HUH KM et al (2005), worked on hydrotropic polymer micelles, consisting of a hydrophilic

PEG shell and a hydrophobic core that contains a significant amount of hydrotropic moieties for

solubilization of poorly soluble drugs such as paclitaxel where the hydrotropic polymer micelles

exhibited a high drug loading capacity with enhanced long-term stability presenting an

alternative and promising approach in formulation of poorly soluble drugs [9].

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MUDIT D et al (2011), worked on preparation of freeze dried crystals of poorly soluble drug,

indomethacin by freeze drying technique using solvent composition of isopropyl alcohol (10ml):

water mixtures in ratio of 50:50. This resulted in decreased crystallinity and improved

micromeritic properties which lead to improved dissolution and solubility compared to the

commercial sample. Thus this method was useful in the formulation of indomethacin tablets by

direct compression method[10].

RAI VK et al (2010), studied the role of various hydrophilic binders for enhancement of

dissolution of a poorly soluble drug, raloxifene hydrochloride (RLX-HCl), using solid oral

dosage form. Hydrophilic binders such as polyvinyl pyrrolidone, hydroxy propyl methyl

Cellulose, hydroxy propyl cellulose were investigated. The formulation using hydrophobic

binder ethyl cellulose showed significant improvement in dissolution behavior of drug [11].

PATEL ND et al (2011), reviewed on lipid based formulations with particular emphasis on self

emulsifying drug delivery system (SEDDS), to improve the oral bioavailability of lipophilic

drugs. It was observed that in SEDDS, the lipid matrix interacts readily with water, forming a

fine particulate oil-in-water (o/w) emulsion and the emulsion droplets delivered the drug to the

gastrointestinal mucosa in the dissolved state, readily accessible for absorption with increase

in AUC.[12].

MAHESHWARI RK et al (2010), worked on a poorly water-soluble drug, frusemide.The

drug was solubilized using hydrotropic blend containing 5 M urea, 1 M sodium acetate and 0.4

M sodium citrate for the spectrophotometric analysis precluding the use of organic solvents

concluding that the proposed method is new, simple, accurate, cost-effective, safe, economic,

precise and can be successfully employed in the routine analysis of frusemide in bulk and

tablets[13].

PATEL A et al (2011), prepared solid dispersion of furosemide to increase the solubility by

using different concentration of polyethylene glycol 4000. Formulation containing

Furosemide/PEG 4000 (1:5) showed 92.4% increase in dissolution after 30 minutes in 0.1 N

HCl compared with pure drug resulting as a promising approach for enhancing solubility and

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dissolution rate due to an increase in wetting properties and surface of drug available for

dissolution[14].

KINI AG et al (2011), prepared microspheres of Piroxicam to improve the solubility and

dissolution using two gradeS of chitosan with different drug polymer ratio by spray‐drying

technique. This resulted in decreased crystallinity and improved the solubility and dissolution

compared with pure piroxicam. Thus this method could be used for formulation of tablets of

piroxicam by direct compression with directly compressible tablet excipients[15].

10.3 OBJECTIVES OF THE STUDY:

The present study is planned with the following objectives:

Preformulation studies of the drugs and polymers and drug-polymer interaction

studies by IR, DSC (Differential scanning calorimetry), X-ray diffraction, etc.

Develop suitable method(s) of estimation of the drug(s).

Enhancing the solubility and permeability of the selected drugs using the

following methods:

a) Chemical modification by salt formation.

b) Physical modification by micronisation technique.

c) Alteration of solvent composition by using co-solvents, and surfactants.

d) Carrier systems such as cyclodextrins, micelles, and liposomes.

Evaluation of the solubility and permeability profile of the drug

Formulation into suitable dosage form(s) and evaluation

The best formulations in each category would be subjected to stability tests as

per ICH guidelines.

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MATERIALS AND METHODS:

Materials:

a) Surfactants (Polyoxyethylene stearate , Deoxycholic acid, Tweens and Spans , Sodium lauryl sulphate , Tween 80, PEG 6000 , Poloxamer 407 , Cremophor RH40).

b) Co-solvents (propylene glycol, ethanol, glycerine, and polyethylene glycol).

c)Polymers (Polyvinylpyrrolidone, PEG-4000, PEG-6000, Carboxymethyl cellulose, Hydroxypropyl cellulose, Guar gum, Xanthan gum, Sodium alginate, Methyl cellulose, HPMC, Dextrin, Cyclodextrins, Galactomannan).

d) Cyclo dextrins (methyl, hydroxypropyl,sulfoalkylated and sulfated derivatives of natural cyclodextrins).

Drug:

Class II drugs in BCS classification (Mebendazole, Griseofulvin etc)

Method:

1)Micronization:

Micronization is reduction of particle size up to micron level. In order to get

better dissolution, there is a need to increase solubility and micronization.It is used as one of the

solubilising tool to increase solubility. By micronization we get uniform and narrow particle size

distribution which is essential for developing uniform dosage form.The following methods

which can be used for achieving micronization are jet milling , solid solution & eutectic

mixtures, microprecipitation & microcrystalization, controlled crystallization, supercritical fluid

technology, spray freezing into liquid and spray freeze dry (SFD).

2)Use of co-solvents:

Co-solvent formulations of poorly soluble drugs can be prepared orally and

parenterally. The most frequently used low toxicity cosolvents for parenteral use are propylene

glycol, ethanol, glycerine, and polyethylene glycol. Dimethylsulfoxide(DMSO) and

dimethylacetoamide (DMA) have been widely used as cosolvents because of their large

solubilization capacity for poorly soluble drugs and their relatively low toxicity.Co-solvents may

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be combined with other solubilization techniques and pH adjustment to further increase

solubility of poorly soluble compounds.

11.1. Source of Data

1) Review of literature from:

a. Journals: such as

-Indian Journal of Pharmaceutical Science

-International Journal of Pharmaceutical.

-Biomaterials.

-Pharmaceutical Research.

-European Journal of Pharmaceutical Sciences.

-Drug Development and Industrial Pharmacy.

b. Internet browsing.

c. Helinet, rguhs.ac.in

2) e-Library: T. John college of pharmacy.

.

11.2. Method of Collection Of Data

• Laboratory studies which include, preformulation studies, formulation and evaluation

studies such as amount of drug released rate kinetics &stability studies etc.

• Data of physiochemical properties of the drug and polymers used such as solubility in

various solvents, pH will be collected through literature search.

11.3. Does the study require any investigation or intervention to be conducted on patients or

other humans or animals? If so, please mention briefly.

-NO-

11.4. Has ethical clearance been obtained from your institution in case of 11.3?

- NOT APPLICABLE-

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12LIST OF REFERENCES:

1.Phanchaxari M, Kaushik S, Telsang S,Enhancement of Solubility and Dissolution property of

Griseofulvin by Nanocrystallization, Int J. Drug Dev. & Res., 3(2) P 180-191 (2011) .

2. Mukherjee S, Patel P, Patel A, Patel H, Patel P, A Review on Solubility Enhancement

Techniques, International Journal Of Pharmaceutical Research And Bioscience, volume1 (1)

(2012).

3. Shukla M, Rathore P, Jain A, Nayak S ,Enhanced Solubility study of Glipizide using different

Solubilization techniques, Int J Pharm Pharm Sci , vol 2, issue2, (2010) .

4.Varshney S, Tiwari A, Negi D, Khulbe P, Singhal P,Solubility Enhancement of Norfloxacin: a

Review, Journal of Sciences, 02(01),(2012).

5. Bansal K, Pant P, Rao P, Padhee K, Sathapathy A and Kochhar P ,Micronization and

Dissolution Enhancement of Norethindrone, International Journal Of Research In Pharmacy And

Chemistry, , 1(3), (2011).

6. Grace X, Latha S, Shanthi S, Reddy C, Comparative study of Different Surfactants for

Solubility Enhancement of Two class ii drugs for Type ii Diabetes mellitus, , Int J Pharm Pharm

Sci , 2(4), (2012).

7. Harti J, Cherrah Y, and Bouklouze A, Improvement of Water Solubility of Josamycin by

Inclusion complex with γ-Cyclodextrin, International Scholarly Research Network,Isrn

Analytical Chemistry,Volume (2012).

8. Nayak A and Panigrahi P, Solubility Enhancement of Etoricoxib by Cosolvency approach ,

International Scholarly Research Network, Isrn Physical Chemistry,Volume (2012).

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9. Huh K, Lee S, Cho Y, Lee J, Jeong J, Park K, Hydrotropic Polymer Micelle system for

Delivery of Paclitaxel, J Control Release ,101 P 59–68 (2005).

10. Mudit D, Keshavarao K, Vamsi Krishna N, Lavanya D, Anil G, Enhancing Solubility and

Dissolution of Indomethacin by Freeze Drying, International Research Journal Of Pharmacy,

(2011).

11. Rai V. k., Rajput BS, Sharma M, Agarwal A, GuptaA and Singh N, Solubility Enhancement

of Poorly water-soluble drug (Raloxifene hydrochloride) by using Different Hydrophilic binders

in Solid dosage form, Pharmacie Globale International Journal Of Comprehensive Pharmacy,

(2010).

12. Patel ND , Patel KV, Panchal LA, Shukla AK, Shelat PK., An Emerging technique for

Poorly Soluble Drugs: Self Emulsifying Drug Delivery System, International Journal Of

Pharmaceutical & Biological Archives, 2(2) P 621-629, (2011).

13. Maheshwari RK, Juneja C and Juneja N, Application of Mixed-Hydrotropic Solubilization

concept in Spectrophotometric analysis of Frusemide in Tablet dosage form” , The Pharma

Research (T. Ph. Res.), 3 P 243-248 (2010).

14.Patel A, Prajapati P, Boghra R, Shah D, Solubility Enhancement of Poorly Aqueous Soluble

Furosemide using PEG-4000 by Solid Dispersion, Asian J Pharm Clin Res (ajpscr) issue 2, vol. 1

P 1-9. (2011).

15. Kini A, Dixit M and Kulkarni PK, Enhancement of Solubility and Dissolution rate of Poorly

Water Soluble drug by Spray Drying using different grade of Chitosan” , Int J Pharm Pharm Sci,

vol 3,2 ,(2011).

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