11

SEMINAR SEMINAR ONON

SOLID DISPERSIONSOLID DISPERSIONPOLYMORPHISMPOLYMORPHISM

UNDERUNDERSOLUBILIZATION & SOLUBILIZED SYSTEMSSOLUBILIZATION & SOLUBILIZED SYSTEMS

PRESENTED BYPRESENTED BY DHAVAL MADAT DHAVAL MADAT

M-PHARM -1 M-PHARM -1 ROLL NO-3 ROLL NO-3

DEPARTMENT OF PHARMACEUTICS AND DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICALPHARMACEUTICAL

TECHNOLOGY TECHNOLOGY L. M. COLLEGE OF PHARMACY. L. M. COLLEGE OF PHARMACY.

22

SOLID DISPERSION:SOLID DISPERSION:

Definition: Definition:

Solid dispersions are prepared to:Solid dispersions are prepared to:

1. To improve drug solubility1. To improve drug solubility

2. To improve drug stability2. To improve drug stability

3. To mask the bitter taste of drug3. To mask the bitter taste of drug

4. To obtain required release profile4. To obtain required release profile

33

Classification of S.D.Classification of S.D. : :

Simple eutectic mixture.Simple eutectic mixture. Solid solution.Solid solution. Glass solution and glass suspension.Glass solution and glass suspension. Amorphous precipitations in a crystalline Amorphous precipitations in a crystalline

carrier.carrier. Compound or Complex formation.Compound or Complex formation. Combinations of previous five types.Combinations of previous five types.

44

Methods of preparation of solid dispersion

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

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

55

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

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

66

Mechanisms for increasing solubility:

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

77

Criteria for selection of :

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

SOLVENTSOLVENT Nontoxic.Nontoxic. Evaporate readily at RT.Evaporate readily at RT. Chemically inert.Chemically inert.

88

Advantage & disadvantage of SD :

ADVANTEGEADVANTEGE Provide rapid dissolution Provide rapid dissolution

rate.rate. Avoids polymorphic Avoids polymorphic

changes.changes. Avoid presystematic Avoid presystematic

metabolismmetabolism Protection by PEG Protection by PEG

against decomposition by against decomposition by salivasaliva

DISADVANTAGEDISADVANTAGE Unstable.Unstable. Changes in crystallinity.Changes in crystallinity. Tackiness.Tackiness.

99

1010

Limitations of S.D.:

Method of Preparation.Method of Preparation.Reproducibility of Physicochemical Reproducibility of Physicochemical

Properties.Properties.Dosage Form Development.Dosage Form Development.Scale up of Manufacturing Processes.Scale up of Manufacturing Processes.Stability.Stability.

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

1111

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

peroxidase present in PEG. peroxidase present in PEG.

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

1212

Breakthroughs in solid dispersion technology:

Two recent breakthroughs,Two recent breakthroughs, The development of technologies to fill S.D. directly The development of technologies to fill S.D. directly

into HGC.into HGC. The avaibility of surface-active and self-emulsifying The avaibility of surface-active and self-emulsifying

carrier.carrier.

eg: 1) Gelucire 44/14 (Gattefosse Corp., France).eg: 1) Gelucire 44/14 (Gattefosse Corp., France).

2) Vitamin E TPGS NF (Eastman , Kingsport, TN).2) Vitamin E TPGS NF (Eastman , Kingsport, TN).

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

1313

1414

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

protein inhibitorprotein inhibitor..Film coated sugar beadsFilm coated sugar beadsGlass thermoplastic system (GTS)Glass thermoplastic system (GTS)Hot melt extrusionHot melt extrusion

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

1515

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 ( ~62°C) 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)( JPS , Vol-92, No:- 3 March 2003)

1616

Other example of eutectic system:

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

Diazepam/PEG 4000, Eutectic composition Diazepam/PEG 4000, Eutectic composition contained contained 17%w/w diazepam.17%w/w diazepam. ( DDIP . 1983, 9, 103-115 )( DDIP . 1983, 9, 103-115 )

1717

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:It is prepared by two methods:

1) Small scale-batch method.1) Small scale-batch method.

2) Twin screw extruder.2) Twin screw extruder.o The drug existed in amorphous state and hardly The drug existed in amorphous state and hardly

recrystallized even after storing at a stressed recrystallized even after storing at a stressed condition (60 C/80% RH for 3 days).condition (60 C/80% RH for 3 days).

o The solubility and BA were improved.The solubility and BA were improved.

( JPS, Vol- 91, No:- 2, Feb 2002)( JPS, Vol- 91, No:- 2, Feb 2002)

1818

The preparation of Enteric solid dispersion in HPMC The preparation of Enteric solid dispersion in HPMC

acetate Succinate using twin-screw extruderacetate Succinate using twin-screw extruder It was found that dissolved HPMCAS retarded the It was found that dissolved HPMCAS retarded the

crystallization of nifedipine in aqueous medium compared crystallization of nifedipine in aqueous medium compared with HPMC phthalate and was a suitable carrier for with HPMC phthalate and was a suitable carrier for preparation of nifedipine solid dispersion.preparation of nifedipine solid dispersion.

Similarly, Indomethacin, nicardipine HCl, oxybutynin HCl Similarly, Indomethacin, nicardipine HCl, oxybutynin HCl with HPMCAS were extruded and there were no crystal with HPMCAS were extruded and there were no crystal peak obtained in DSC.peak obtained in DSC.

CONCLUSION:CONCLUSION: HPMCAS can be used to improve the HPMCAS can be used to improve the dissolution of poorly soluble comp. & a twin-screw extruder dissolution of poorly soluble comp. & a twin-screw extruder is useful for efficient preparation of solid dispersion.is useful for efficient preparation of solid dispersion.

( C.A. , VOL-142, No:- 9, FEB. 28, 2005, 162218e )( C.A. , VOL-142, No:- 9, FEB. 28, 2005, 162218e )

1919

Composition of pharmaceutical preparation containing solubilized ibuprofen & mfg. method thereof.

Co precipitation of IB by dissolving 10-80% of IB & 1-Co precipitation of IB by dissolving 10-80% of IB & 1-20% of PVP in 20-85% of ethanol.20% of PVP in 20-85% of ethanol.

Drying the solution.Drying the solution. Mixing 10-90 % of Co-ppt with 1.0-20% of a Mixing 10-90 % of Co-ppt with 1.0-20% of a

sweetener, 1.0-60% of an excipient, 1.0-30% of sweetener, 1.0-60% of an excipient, 1.0-30% of binder, 0.1-5.0% of lubricant & 0.1-25% of binder, 0.1-5.0% of lubricant & 0.1-25% of disintegrater.disintegrater.

( C.A. Vol-142, No:-12, March 21, 2005, 225744w )( C.A. Vol-142, No:-12, March 21, 2005, 225744w )

2020

Preparation & evaluation of S D of

Naproxen. Carriers used were PVP, PEG 4000, PEG 6000, Carriers used were PVP, PEG 4000, PEG 6000,

PEG20000, Methyl cellulose, PEG20000, Methyl cellulose, ββ –CD. –CD. Solvent evaporation method was used.Solvent evaporation method was used. The order of increase of dissolution by carriers was The order of increase of dissolution by carriers was

found:found: ββ-CD > M C > PVP > PEG4000 > PEG6000 > -CD > M C > PVP > PEG4000 > PEG6000 >

PEG20000.PEG20000. SD were formulated into capsules with usual additives & SD were formulated into capsules with usual additives &

confirmed that these did not hinder the dissolution confirmed that these did not hinder the dissolution characteristic & complied with USP standards.characteristic & complied with USP standards.

( JPS , Jan- Feb 2005, page 26)( JPS , Jan- Feb 2005, page 26)

2121

Future Prospects of S.D.:

New method of preparation.New method of preparation.Scale up and validation of technique.Scale up and validation of technique.Development of Sustained and controlled Development of Sustained and controlled

release preparation.release preparation. Identification of newer carrier.Identification of newer carrier. Identification of vehicle or excipient that Identification of vehicle or excipient that

retard or prevent crystallization.retard or prevent crystallization.

2222

Sustained release solid dispersions

o Nifedipine with anionic polymers such as HPMC Nifedipine with anionic polymers such as HPMC cellulose phthalate & methacrylic acid-methacrylic cellulose phthalate & methacrylic acid-methacrylic acid methyl ester co-polymer.acid methyl ester co-polymer.

(Chem. Phar. Bull.: 33:1615-1619,1985)(Chem. Phar. Bull.: 33:1615-1619,1985)

o Thioridazine Hcl with Pectin.Thioridazine Hcl with Pectin.

( Chem. Phar. Bull. 34:327-332,1986( Chem. Phar. Bull. 34:327-332,1986))

2323

In 1967 term polymorphism was In 1967 term polymorphism was coined by coined by AGUIAR ETALAGUIAR ETAL..

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

2424

Classification of polymorphsClassification of polymorphs Enantiotropic Can be reversibly Can be reversibly

changed into another changed into another form by altering the form by altering the temperature or temperature or pressure.pressure.

E.g. Sulfur E.g. Sulfur

Monotropic Unstable at all Unstable at all

temperatures and temperatures and pressures.pressures.

e.g glyceryl e.g glyceryl stearatestearate

2525

Impact of polymorphism on solubility:

Table: 1 Anhydrate/Hydrate Solubility Ratio

No. Compound Solubility ratio

1. Erythromycin (A/Di ) 2.2

2. Piroxicam (A/H) 2.2

3. Theophylline 1.9

4. LY334370 HCL ( Di/A) 6.0

2626

Table:2 Solubility RatioTable:2 Solubility RatioCompound Solubility RatioQuinolon dvt 1

Glybuzole (37) 1

Etoposide (28) 1.9

Lamivudine (7) 1.2

Fluconazole (ІІ/І) 1.1

Piroxicam (ІІ/ІІІ) 1.3

Methyl Prednisolone (41) 1.7

2727

Polymorphism of experimental Polymorphism of experimental hypertensive drug:hypertensive drug:

Polymorph 1 – formed by recrystallization from Polymorph 1 – formed by recrystallization from methanol, water, HCL solution.methanol, water, HCL solution.

Polymorph 2 – formed by recrystallization from Polymorph 2 – formed by recrystallization from isopropanol, DMF, DMA.isopropanol, DMF, DMA.

The dissolution rate & peak solubility of form 2 is The dissolution rate & peak solubility of form 2 is 3 to 4 times higher than form 1.3 to 4 times higher than form 1.

( ( JPS , 1987, 61, page-1423-1429JPS , 1987, 61, page-1423-1429 ) )

2828

Polymorphism in nitrofurantoin:Polymorphism in nitrofurantoin:

Three polymorph,Three polymorph, pseudopolymorh, pseudopolymorh,

anhydrate, anhydrate, monohydrate.monohydrate.

o Max. solubility is Max. solubility is obtained with pseudo.obtained with pseudo.

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

2929

Polymorphism of Roxifiban:Polymorphism of Roxifiban:

Two polymorphic forms.Two polymorphic forms. Solubility increased in Solubility increased in

binary blends of binary blends of acetonitrile and N,N, acetonitrile and N,N, dimethyl acetamide. dimethyl acetamide.

As DMA in acetonitrile As DMA in acetonitrile increased,solubility of increased,solubility of both forms of Roxifiban both forms of Roxifiban also increased.also increased.

(JPS ,Vol-91, No:- 12, (JPS ,Vol-91, No:- 12, Dec-2002)Dec-2002)

3030

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

  

1.1.          

1.      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 37°C, Form B was 4 times more soluble than form A and form C was 2 times more soluble than form A. 

3131

1. Cortisone acetate aq. Suspension             exists in 5 diff polymorphs. form 2 is more exists in 5 diff polymorphs. form 2 is more

soluble than form 5. soluble than form 5. Form 5 is more stable one, and hence get caked out Form 5 is more stable one, and hence get caked out

on storage. Also, four out of five are unstable in on storage. Also, four out of five are unstable in presence of water and convert to fifth one (stable one).presence of water and convert to fifth one (stable one).

Heating, grinding under water and suspension in water Heating, grinding under water and suspension in water do not prevent the above conversion. Therefore the do not prevent the above conversion. Therefore the remedy will be:remedy will be:

    This conversion should first be allowed and than This conversion should first be allowed and than final suspension should be prepared.final suspension should be prepared.

OROR     Use the comp. which would not allow the growth of Use the comp. which would not allow the growth of

crystals.crystals. e.g. methyl cellulose, pectin, PVP, gelatin, sodium e.g. methyl cellulose, pectin, PVP, gelatin, sodium

alginate, sodium cmc etc.alginate, sodium cmc etc.

3232

1.1. Ampicillin oral suspensionAmpicillin oral suspension             Aq. Solubility of anhydrous form is Aq. Solubility of anhydrous form is

20% more than that of trihydrate form.20% more than that of trihydrate form.             In vivo experiments Were done In vivo experiments Were done

where anhydrous and trihydrate form of where anhydrous and trihydrate form of the drug were given as oral suspension the drug were given as oral suspension or capsules. or capsules.

The anhydrous form produce higher The anhydrous form produce higher peak in the blood serum than trihydrate peak in the blood serum than trihydrate form.  form.  

3333

1.1. Chloramphenicol palmitate suspensionChloramphenicol palmitate suspension             The drug contains four polymorphs: three (A, B, The drug contains four polymorphs: three (A, B,

C) are crystalline and one is amorphous form.C) are crystalline and one is amorphous form.             After single oral ingestion of suspension with After single oral ingestion of suspension with

quantity equivalent to 1.5 gm chloremphenicol, the quantity equivalent to 1.5 gm chloremphenicol, the highest mean blood level after 24 hr were obtained highest mean blood level after 24 hr were obtained with form B only. While blood level decrease with with form B only. While blood level decrease with increase in conc. of form A. increase in conc. of form A.

            This is because form A is more stable at temp. This is because form A is more stable at temp. less than 50 C , form B is more soluble one under the less than 50 C , form B is more soluble one under the same temp. range.same temp. range.

3434

1. Cimetidine:             It contains four polymorphs : A,B, C, DIt contains four polymorphs : A,B, C, D             BA as well as ulcer inhibiting action in rats were BA as well as ulcer inhibiting action in rats were

studied. studied.             Plasma conc., curve of form A and B were Plasma conc., curve of form A and B were

similar. AUC of form C was 1.5 and 1.4 times larger similar. AUC of form C was 1.5 and 1.4 times larger than that of form A and B respectively. Also the ulcer than that of form A and B respectively. Also the ulcer inhibiting action of form C at low doses (12.5 mg/kg) inhibiting action of form C at low doses (12.5 mg/kg) was more than that of other forms.was more than that of other forms.

Therefore looking over ulcer inhibiting action of form C, Therefore looking over ulcer inhibiting action of form C,

it was proved to be more effective than other forms.it was proved to be more effective than other forms.

3535

References: 1.            C.A. VOL- 142, NO:- 9. FEB- 28, 2005, 162219f. 2.            IJPS , 1986, VOL-42 , page-138. 3.            JPS , VOL-88, NO:- 10, Oct- 1999, Page-1058. 4.            JPS , 1987, 61, page-1423-1429. 5.            Chem.Pharm. Bull. 1991, 39, page-2667. 6.            JPS ,VOL-91, NO:- 12, DEC 2002. 7.            JPS , VOL-92, NO:- 3 MARCH 2003. 8.      JPS, JAN- FEB 2005, page 26. 9.            JPS, VOL. 94, NO. 5, MAY 2005, Page 929. 10.       JPS, VOL. 60, NO. 9, SEPT 1971, Page 1281.

11.       Encyclopedia of pharmaceutical technology, Volume 3.BY James

Swarbrick & James C. Boylan

3636

Study questions:Study questions:

1.1. What is solid dispersion? Give the detailed What is solid dispersion? Give the detailed note on classification of solid dispersion.note on classification of solid dispersion.

2.2. How the solid dispersions can be How the solid dispersions can be evaluated?evaluated?

3.3. What are the recent breakthroughs in solid What are the recent breakthroughs in solid dispersion technology?dispersion technology?

4.4. Discuss the limitations of solid dispersion.Discuss the limitations of solid dispersion.

5.5. Give the importance of polymorphism as Give the importance of polymorphism as tool for increasing solubility with suitable tool for increasing solubility with suitable examples.examples.

3737

THANK YOU.THANK YOU.