1

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

2

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.

3

Melting / fusion method.Solvent method.Melting-solvent method. ( Encyclopedia of P T, VOL- 3, page 337)

4

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)

5

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

6

CARRIER Thermal and air

stable. Soluble. Recrystallizing

property. Low vapour pressure. Compatible with

drug. Low melting point.

SOLVENTNontoxic.Evaporate readily at

RT.Chemically inert.

7

ADVANTEGE Provide rapid

dissolution rate. Avoids polymorphic

changes. Avoid presystematic

metabolism Protection by PEG

against decomposition by saliva

DISADVANTAGE Unstable. Changes in

crystallinity. Tackiness.

8

9

Method of Preparation. Reproducibility of Physicochemical

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

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

10

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 )

11

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 )

12

13

Film coated sugar beadsGlass thermoplastic system (GTS)

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

14

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.

15

16

It is prepared by two methods: 1) Small scale-batch method. 2) Twin screw extruder.o The drug existed in amorphous state and

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

o The solubility and BA were improved. ( JPS, Vol- 91, No:- 2, Feb 2002)

17

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 )

18

Co precipitation of IB by dissolving 10-80% of IB & 1-20% 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 )

19

Carriers used were PVP, PEG 4000, PEG 6000, PEG20000, Methyl cellulose, β –CD.

Solvent evaporation method was used. The order of increase of dissolution by carriers

was found: β-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)

20

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.

21

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

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

o Thioridazine Hcl with Pectin.

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

22

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

23

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

24

Table: 1 Anhydrate/Hydrate Solubility Ratio

25

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

26

Compound 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

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 )

27

Three polymorph, pseudopolymorh,

anhydrate, monohydrate.

o Max. solubility is obtained with pseudo.

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

28

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)

29

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

30

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. 

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.

OR1.   Use the comp. which would not allow the

growth of crystals.2. e.g. methyl cellulose, pectin, PVP, gelatin,

sodium alginate, sodium cmc etc.

31

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.  

32

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.

33

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.

34

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

35

THANK YOU.

36