SEMINAR ON SOLID DISPERSION POLYMORPHISM

UNDER SOLUBILIZATION & SOLUBILIZED SYSTEMS

PRESENTED BY DHAVAL MADAT M-PHARM -1 ROLL NO-3 DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L. M. COLLEGE OF PHARMACY.
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SOLID DISPERSION:

Definition:

Solid dispersions are prepared to:

1. To improve drug solubility 2. To improve drug stability 3. To mask the bitter taste of drug 4. To obtain required release profile
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Classification of S.D. :

Simple eutectic mixture. Solid solution. Glass solution and glass suspension. Amorphous precipitations in a crystalline carrier. Compound or Complex formation. Combinations of previous five types.

Methods of preparation of solid dispersion

Melting

/ fusion method. Solvent method. Melting-solvent method.

( Encyclopedia of P T, VOL- 3, page 337)

Evaluation of solid dispersion :

Thermal analysis. 1. Cooling curve method. 2. Thaw melt method. 3. Thermo microscopic method. 4. DSC or DTA. 5. Zone melting method. X-ray diffraction I.R., NMR. Dissolution rate and diffusion rate method Microscopic method Thermodynamic method

( IJPS , 1986, Vol-42 , page-138)

Mechanisms for increasing solubility:

Reduction of particle size. Solubilization effect of carrier material on drug. Improved wettability and dispersibility of drug. Formation of metastable dispersion.

Criteria for selection of :

CARRIER Thermal and air stable. Soluble. Recrystallizing property. Low vapour pressure. Compatible with drug. Low melting point.

SOLVENT Nontoxic. Evaporate readily at RT. Chemically inert.

Advantage & disadvantage of SD :

ADVANTEGE Provide rapid dissolution rate. Avoids polymorphic changes. Avoid presystematic metabolism Protection by PEG against decomposition by saliva

DISADVANTAGE Unstable. Changes in crystallinity. Tackiness.

Limitations of S.D.:
Method of Preparation. Reproducibility of Physicochemical Properties. Dosage Form Development. Scale up of Manufacturing Processes. Stability.

( JPS , Vol-88, No:- 10, Oct- 1999 )

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Stability:
Crystallization on aging. e.g. Griseofulvin-PEG 6000 Decrease in dissolution rate on aging. e.g. Nifedipine-Nicotinamide-HPMC SD. Chemical degradation. e.g. Corticosteroid, Oxidation due to peroxidase present in PEG.

( JPS , Vol-88, No:- 10, Oct- 1999 )

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Breakthroughs in solid dispersion technology:

Two recent breakthroughs,

The development of technologies to fill S.D. directly into HGC. The avaibility of surface-active and self-emulsifying carrier. eg: 1) Gelucire 44/14 (Gattefosse Corp., France). 2) Vitamin E TPGS NF (Eastman , Kingsport, TN).

( JPS , VOL- 88, No:- 10, Oct- 1999 )

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The three new different S.D. formulations for novel microsomal triglyceride transfer protein inhibitor.
Film

coated sugar beads Glass thermoplastic system (GTS) Hot melt extrusion

(JPS May 2004, 1217, Vol. 93. No.528.)

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Eutectic Mixtures of PEG & Fenofibrate:

PEG is an ideal inactive component for preparing simple binary eutectic mixtures because, it has, 1) Low entropy of fusion ( ~0.0076 J/mol-K) 2) Low melting point ( ~62C) 3) Miscibility with drug 4) covalent crystalline lattice. o S D of PEG-Fenofibrate when characterized , revealed that formation of eutectic mixture at 20-25%(w/w) Fenofibrate . o Eutectic crystallization led to the formation of irregular microstructure, in which, Fenofibrate crystals were found to be less than 10 micron size. o On aging, the dissolution rate of S D containing 15%(w/w) remained unaltered.

( JPS , Vol-92, No:- 3 March 2003)

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Other example of eutectic system:

Tolbutamide/mannitol,eutectic composition contained 94%w/w Tolbutamide. ( Pharmazie 1975, 30, 788-792)

Diazepam/PEG 4000, Eutectic composition contained 17%w/w diazepam. ( DDIP . 1983, 9, 103-115 )
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Improvement of solubility of poorly water-soluble drug, TAS-301, by its Melt-Adsorption on a porous Calcium Silicate, Florite R RE.

It is prepared by two methods: 1) Small scale-batch method. 2) Twin screw extruder. The drug existed in amorphous state and hardly recrystallized even after storing at a stressed condition (60 C/80% RH for 3 days). The solubility and BA were improved. ( JPS, Vol- 91, No:- 2, Feb 2002)
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The preparation of Enteric solid dispersion in HPMC acetate Succinate using twin-screw extruder

It was found that dissolved HPMCAS retarded the crystallization of nifedipine in aqueous medium compared with HPMC phthalate and was a suitable carrier for preparation of nifedipine solid dispersion. Similarly, Indomethacin, nicardipine HCl, oxybutynin HCl with HPMCAS were extruded and there were no crystal peak obtained in DSC.

CONCLUSION: HPMCAS can be used to improve the dissolution of poorly soluble comp. & a twin-screw extruder is useful for efficient preparation of solid dispersion. ( C.A. , VOL-142, No:- 9, FEB. 28, 2005, 162218e )
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Composition of pharmaceutical preparation containing solubilized ibuprofen & mfg. method thereof.

Co precipitation of IB by dissolving 10-80% of IB & 120% of PVP in 20-85% of ethanol. Drying the solution. Mixing 10-90 % of Co-ppt with 1.0-20% of a sweetener, 1.0-60% of an excipient, 1.0-30% of binder, 0.1-5.0% of lubricant & 0.1-25% of disintegrater. ( C.A. Vol-142, No:-12, March 21, 2005, 225744w )
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Preparation & evaluation of S D of Naproxen.

Carriers used were PVP, PEG 4000, PEG 6000, PEG20000, Methyl cellulose, CD. Solvent evaporation method was used. The order of increase of dissolution by carriers was found: -CD > M C > PVP > PEG4000 > PEG6000 > PEG20000. SD were formulated into capsules with usual additives & confirmed that these did not hinder the dissolution characteristic & complied with USP standards. ( JPS , Jan- Feb 2005, page 26)
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Future Prospects of S.D.:

New method of preparation. Scale up and validation of technique. Development of Sustained and controlled release preparation. Identification of newer carrier. Identification of vehicle or excipient that retard or prevent crystallization.

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Sustained release solid dispersions

o

Nifedipine with anionic polymers such as HPMC cellulose phthalate & methacrylic acidmethacrylic acid methyl ester co-polymer. (Chem. Phar. Bull.: 33:1615-1619,1985)

Thioridazine Hcl with Pectin. ( Chem. Phar. Bull. 34:327-332,1986)

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In 1967 term polymorphism was coined by AGUIAR ETAL.

Defination:-It is the ability of any compound or element to crystallize as one or more distinct crystal species with different internal lattice.

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Classification of polymorphs

Enantiotropic Can be reversibly changed into another form by altering the temperature or pressure. E.g. Sulfur

Monotropic Unstable at all temperatures and pressures. e.g glyceryl stearate

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Impact of polymorphism on solubility:

Table: 1 Anhydrate/Hydrate Solubility Ratio
No.
1. 2. 3. 4.

Compound
Erythromycin (A/Di ) Piroxicam (A/H) Theophylline LY334370 HCL ( Di/A)

Solubility ratio
2.2 2.2 1.9 6.0

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Table:2 Solubility Ratio

Compound
Quinolon dvt Glybuzole (37) Etoposide (28) Lamivudine (7) Fluconazole (/) Piroxicam (/) Methyl Prednisolone (41)

Solubility Ratio
1 1 1.9 1.2 1.1 1.3 1.7

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Polymorphism of experimental hypertensive drug:

Polymorph 1 formed by recrystallization from methanol, water, HCL solution. Polymorph 2 formed by recrystallization from isopropanol, DMF, DMA. The dissolution rate & peak solubility of form 2 is 3 to 4 times higher than form 1. ( JPS , 1987, 61, page-1423-1429 )

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Polymorphism in nitrofurantoin:

Three polymorph, pseudopolymorh, anhydrate, monohydrate. Max. solubility is obtained with pseudo.

(Chem.Pharm. Bull. 1991, 39, page-2667)

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Polymorphism of Roxifiban:

Two polymorphic forms. Solubility increased in binary blends of acetonitrile and N,N, dimethyl acetamide. As DMA in acetonitrile increased,solubility of both forms of Roxifiban also increased. (JPS ,Vol-91, No:- 12, Dec-2002)
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1.

Phenylbutazone It exists in four different polymorphs: ,, ,V . Solubility results shows that form-I is more soluble as compared to others in phosphate buffer at 36 C.

Cilostazol the only crystalline form reported has poor solubility in acidic, basic, and aqueous media. To improve the solubility, an investigation into potential polymorphic form was initiated. During this study, an amorphous and two polymorphic form were discovered. calorimetry data indicated that at 37C, Form B was 4 times more soluble than form A and form C was 2 times more soluble than form A.
1.
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1.

Cortisone acetate aq. Suspension exists in 5 diff polymorphs. form 2 is more soluble than form 5. Form 5 is more stable one, and hence get caked out on storage. Also, four out of five are unstable in presence of water and convert to fifth one (stable one). Heating, grinding under water and suspension in water do not prevent the above conversion. Therefore the remedy will be: This conversion should first be allowed and than final suspension should be prepared. OR Use the comp. which would not allow the growth of crystals. e.g. methyl cellulose, pectin, PVP, gelatin, sodium alginate, sodium cmc etc.
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1.

Ampicillin oral suspension

Aq. Solubility of anhydrous form is 20% more than that of trihydrate form. In vivo experiments Were done where anhydrous and trihydrate form of the drug were given as oral suspension or capsules. The anhydrous form produce higher peak in the blood serum than trihydrate form.
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1.

Chloramphenicol palmitate suspension

The drug contains four polymorphs: three (A, B, C) are crystalline and one is amorphous form. After single oral ingestion of suspension with quantity equivalent to 1.5 gm chloremphenicol, the highest mean blood level after 24 hr were obtained with form B only. While blood level decrease with increase in conc. of form A. This is because form A is more stable at temp. less than 50 C , form B is more soluble one under the same temp. range.

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1.

Cimetidine:
It contains four polymorphs : A,B, C, D BA as well as ulcer inhibiting action in rats were studied. Plasma conc., curve of form A and B were similar. AUC of form C was 1.5 and 1.4 times larger than that of form A and B respectively. Also the ulcer inhibiting action of form C at low doses (12.5 mg/kg) was more than that of other forms. Therefore looking over ulcer inhibiting action of form C, it was proved to be more effective than other forms.
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References:

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

C.A. VOL- 142, NO:- 9. FEB- 28, 2005, 162219f. IJPS , 1986, VOL-42 , page-138. JPS , VOL-88, NO:- 10, Oct- 1999, Page-1058. JPS , 1987, 61, page-1423-1429. Chem.Pharm. Bull. 1991, 39, page-2667. JPS ,VOL-91, NO:- 12, DEC 2002. JPS , VOL-92, NO:- 3 MARCH 2003. JPS, JAN- FEB 2005, page 26. JPS, VOL. 94, NO. 5, MAY 2005, Page 929. JPS, VOL. 60, NO. 9, SEPT 1971, Page 1281. Encyclopedia of pharmaceutical technology, Volume 3.BY James

Swarbrick & James C. Boylan

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Study questions:
1.

2.

3.

4. 5.

What is solid dispersion? Give the detailed note on classification of solid dispersion. How the solid dispersions can be evaluated? What are the recent breakthroughs in solid dispersion technology? Discuss the limitations of solid dispersion. Give the importance of polymorphism as tool for increasing solubility with suitable examples.

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THANK YOU.

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