Enhancement of Solubility By Solid Dispersion- Presented By Mr.Ajinkya Nikam (National Award Winner Presentation)

Prepared by

Ajinkya N. Nikam

(F.Y.M.Pharm, Sem-I)

[email protected]

Department of PharmaceuticsH. R. PATEL INSTITUTE OF PHARMACEUTICAL EDUCATION & RESEARCH

SHIRPUR (M.S.) 425 405

2015 – 2016

Guided by

Dr. P. K. Deshmukh

Head of Department

ENHANCEMENT OF SOLUBILITY BY SOLID DISPERSION

05/10/2015Enhancement of solubility by Solid Dispersion A.N.Nikam2

Sr. No. Content Slide no.

1 Introduction 3

2 What is Solubility? 4

3 Solid Dispersion 5

4 Need of Solid Dispersion 6

5 Solid Dispersion Methods 7

6 Characterization of Solid Dispersion 17

7 Advantages 18

8 Disadvantages 19

9 Application 20

10 Marketed Formulations 21

11 Summary 22

12 Conclusion 23

13 References 24,25,26

14 Trivia 27

15 Acknowledgment 28

Table of Contents

Introduction1

05/10/2015Enhancement of solubility by Solid Dispersion A.N.Nikam

3

Therapeutic effectiveness of a drug

depends upon the bioavailability and

ultimately upon the solubility of drug

molecules.

Solubility is one of the important

parameter to achieve desired concentration

of drug in systemic circulation for

pharmacological response to be shown.

Important!

Solid Dispe

Important!

Currently only 8% of new drugcandidates have both highsolubility and permeability.

What is Solubity?2,3


4

The transfer of molecules or ions from a solidstate into solution is know as dissolution.

The extent (maximum) to which dissolutionproceeds under a given set of experimentalconditions is referred to as the solubility of thesolute in the solvent.

Important!

Quantitatively

Concentration of

Solute

Saturated Solution

Qualitatively

spontaneous interaction

of substances

homogenous molecular

dispersion

Solid Dispersion4,16,17

05/10/2015

5

Enhancement of solubility by Solid Dispersion A.N.Nikam

The term solid dispersions refer to a group of solid products

consisting of at least two different components, generally a

hydrophilic matrix and a hydrophobic drug.

According to Chiou and Rielman (1971) , a pharmaceutical

solid dispersion is ‘the dispersion of one or more active

ingredients in an inert carrier matrix at solid state prepared by

melting (fusion), solvent or melting solvent method’.

Further, Corrigan, 1985, defined solid dispersions as products

formed by converting a drug-carrier combination in fluid state to

the solid state. Hydrophilic polymers are the most used carrier

materials for the preparation of solid dispersions.

Important!

Solid Dispersion= Hydrophobic Drug + Hydrophilic Matrix

Need of Solid dispersion3,4

05/10/2015

6


In Biopharmaceutical Classification System (BCS) drugs

with low aqueous solubilty and high membrane permeability

are categorized as Class II drugs.

Therefore, Solid Dispersion technologies are particularly

promising for improving the oral absorption and

bioavailabilty of Class II Drugs.

Important!

Now a days More than 40%

drugs are lipophilic & having a

problem of poor water solubility.

Solid Dispersion Methods4-11


7

F u s i o n M e t h o d

M e l t E x t r u s i o n

S o l v e n t E v a p o r a t i o n

Ly o p h i l i z a t i o n

S p r a y D r y i n g

Fusion Method6


8

Fusion or Melting method was first introduced by Sekiguchi

et al. in 1961 where the drug was melted in a carrier and after

cooling the dry mass obtained was pulverized and sieved to

obtain powder.

They prepared the SDs of Sulfathiazole in different carriers

(e.g. ascorbic acid, acetamide, nicotinamide, nicotinic acid,

succinimide and urea) by the formation of melt of different

drug carrier mixtures.

Cooling of the drug-carrier melt was done on ice bath with

continuous stirring until the dry mass was obtained.

Important!

Method developed by

Sekiguchi et al. in 1961 was the

first one among the SOLID

DISPERSION range.


9

Hot Melt Extrusion is essentially same as the fusion

method except that intense mixing of component is

induced by extruder.

However, compared to the traditional fusion

method, this technique offers the possibility of

continuous production, which makes it suitable for

large scale production.

Furthermore, the product is easier to handle at the

outlet of the extruder the shape can be adapted to

the next processing step without grinding.Figure 1: The leistritz twin screw extruder

Hot Melt Extrusion Technology 4,6,7

Important!

Thermo-sensitive drugs &

carrier would not be used in this

technique as they will be

subjected to degradation

(2009 Apr) Solid dispersions-a review - Pak J Pharm Sci, 22(2), 234-246.pdf

ChronYoungSci3295-5421362_150333.pdf

Fig 2. Diagramatic representation of Hot Melt Extrusion technique

Homogeneous mixture of active, polymer

plasticizer, surfactant

Hot Melt Extrusion Technique

05/10/2015

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05/10/2015Enhancement of solubility by Solid Dispersion A.N.Nikam11

Hot Melt Extrusion Technology

Solvent Evaporation Method8


12

In this Method of Solvent Evaporation, the drug and carrier

are dissolved in common solvent, and then the solvent is

evaporated under vacuum to produce a solid.

Example, solid solution of the highly lipophilic β-carotene

in the highly water soluble carrier povidone.

Important!

Tachibana and Nakamura werethe first to dissolve both thedrug and the carrier in acommon solvent and thenevaporate the solvent undervacuum to produce a solid.

DRUG + CARRIER

Same Solvent

Evaporation

Under Vacuum

Solid Remains

195727.pdf

Lyophilization Technique9,10


13

Lyophilization has been thought of a molecular mixing

technique where the drug and carrier are co dissolved in a

common solvent, frozen and sublimed to obtain a

lyophilized molecular dispersion.

This technique was proposed as an alternative method to

solvent evaporation.

Its applicable for the thermolabile or otherwise product

unstable in aqueous solutions for prolonged storage

periods, but that are stable in the dry state.

Sublimation of water can take place at pressures and

temperature below triple point

Important!

TRIPLE POINT?The temperature and pressure atwhich 3 phases (Gas, Solid,Liquid) of substance coexist inthermodynamic equilibrium.

Lyophilization Freeze Drying - An Review.pdf

Lyophilization Cycle


14

Sample

Preparation Freezing

Primary

Drying

Secondary

Drying

Final

Product

Annealing

Fig 3. Lyophilization Cycle

Lyophilization Freeze Drying - An Review.pdf

Spray Drying5,11


15

Figure 4: An illustration of a spray drying technique

Spray drying is an efficient technology for solid

dispersion manufacturing since it allows extreme rapid

solvent evaporation leading to fast transformation of an

API-carrier solution to solid API-carrier particles.Important!

The first use of drying ofproducts from an atomizedliquid stream was already doneby Percy in 1872 (Percy, 1872).And he got patent for the same.

ChronYoungSci3295-5421362_150333.pdf

mailto:[email protected]

Spray Drying Technique


16

Characterization of solid dispersions12,13


17

Several techniques have been available to investigate the molecular arrangement in solid

dispersions.

However, most effort has been put in to differentiate between amorphous and crystalline

material.

Various methods include,

DSC

Powder X-ray diffraction method (Sharper diffraction peaks = crystalline material.)

Spectroscopic methods (FTIR)

Microscopic method (Hot-stage microscopy) and

In-vitro dissolution studies.

ADVANTAGES OF SOLID DISPERSIONS14


18

Generally, solid dispersion is mainly used

1. To reduced particle size.

2. To improve wettability.

3. To improve porosity of drug.

4. To decrease the crystalline structure of drug in to amorphous form.

5. To improve dissolvability in water of a poorly water-soluble drug in a

pharmaceutical.

Disadvantages14


19

Laborious and expensive method of preparation.

Reproducibility of physical characteristics.

Difficulty in incorporating into formulation of dosage

form.

Stability of drug and vehicle.

Important!

Phase seperation can be

prevented by maintaining a low

molecular mobility of matrix &

drug during preparation.


20

To increase the solubility of poorly soluble drugs thereby

enhance the dissolution rate, absorption and

bioavailability.

To obtain a homogeneous distribution of a small amount

of drug in solid state.

To increase bioavailability of drugs.

Pharmaceutical Applications of Solid dispersion4,15

Important!

In spite of almost several year

of research on solid dispersion,

their commercial applications

are limited. Only Few products

are being marketed so far.

Marketed Products4


21

Sr.

No

Brand Name Manufacturer API Carrier

1 Gris-PEG Novartis Griseofulvin PEG*

2 Cisamet Lily Nabilone PVP**

3 Sporanox Janseen Pharmaceutica Itraconazole PEG 20.000,

HPMC***

*PEG - Polyethylene gycol

**PVP - Polyvinylpyrrolidone

***HPMC - Hydroxypropyl Methylcellulose

Summary


22

What is Solubility?

Solid Dispersion

Need of Solid Dispersion Solid Dispersion Methods

Characterization of Solid Dispersion

Advantages& Disadvantages

Application

Marketed Formulations

Conclusion


23

Solid Dispersion is a best method to deliver a lipophilic drug by oral route.

Solubility enhancement of poorly water soluble drugs remains one of most

challenging aspects of drug development.

The solid dispersion method is one of the effective approaches to achieve the goal

of solubility enhancement of poorly water soluble drugs.

Various techniques, are successfully used for the preparation of solid dispersions in

the lab scale and can be used at industrial scale also.

References


24

1. James K; “Solubility and related properties”, vol. 28, Marcel Dekker, Newyork, 986, pp.127 –146, 355 – 395.

2. PHARMACEUTICS: The Science of Dosage Form Design, Edited by M. E. Aulton, 2nd Edition, Churchill Livingstone

Publication, Elsevier Limited, Page No. 16.

3. Kumar B. P., Ramanamurthy K. V., Sahu R.K., “Journal of Chemical and Pharmaceutical Science”, Vol. 4 Issue 4, October2011,

Pages170-179

4. Dhirendra K, Lewis S, Udupa n, Atin N, “Solid dispersions-a review” - Pak J Pharm Sci Vol 22(2) (2009 Apr) , 234-246

5. Paudel, A., et al., Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: Formulation and process

considerations. Int J Pharmaceut (2012), http://dx.doi.org/10.1016/j.ijpharm.2012.07.015

6. Jishnu Vijay et al., A basic insight into the stability and manufacturing aspects of solid dispersions, Vol. 3 | Issue 2 | Apr-Jun 2012,

IP: 64.233.173.174]

7. www.youtube.com/watch?V=uIIMmyIiF70 (cited on 2.05.2015)

8. Ketan T. Savjani, et al, Drug Solubility: Importance and Enhancement Techniques, ISRN Pharmaceutics,Volume 2012, Article ID

195727, doi:10.5402/2012/195727

http://www.youtube.com/watch?V=uIIMmyIiF70

Refereces contd..


25

9. Ladan Akbarpour Nikghalb et al, Solid Dispersion: Methods and Polymers to increase the solubility of poorly soluble

drugs, Journal of Applied Pharmaceutical Science Vol. 2 (10), pp. 170-175, October, 2012, DOI:

10.7324/JAPS.2012.21031, ISSN 2231-3354.

10. GR.Nireesha et al. Lyophilization/Freeze Drying - An Review, INTERNATIONAL JOURNAL OF NOVEL TRENDS IN

PHARMACEUTICAL SCIENCES, VOLUME 3 | NUMBER 4 | OCT | 2013 ,ISSN: 2277 – 2782

11. www.youtube.com/watch?v=Oo4ZCjHnaRw (cited on 4.10.2015)

12. Iswarya Sridhar, et al,“Solid Dispersions: an Approach to Enhance Solubility of poorly Water Soluble Drug”Journal of

Scientific and Innovative Research 2013; 2 (3): 685-694

13. Singh et al., A review on solid dispersion, Int. J. of Pharm. & Life Sci. (IJPLS), Vol. 2, Issue 9: Sep.: 2011, 1078-1095,

ISSN: 0976-7126

14. Mogal S et al., Solid dispersion technique for improving solubility of some poorly soluble drugs,Der Pharmacia Lettre,

2012, 4 (5):1574-1586

15. Kalia A., Poddar M., “International Journal of Pharmacy and Pharmaceutical science” 2011, Vol.3, Issue 4.

http://www.youtube.com/watch?v=Oo4ZCjHnaRw

References contd..


26

16. Chiou W.L. et al., Pharmaceutical applications of solid dispersion systems, Vol 60, issue 9, september

1971.

17. Corrigan et al., mechanism of dissolution of fast release solid dispersions, Vol 11, issue2-3, Oct 20, 1985

Trivia..


27

What is Solid Dispersion?

1. Lipophilic drug + Lipophilic Carrier

2. Lipophilic drug + Hydrophilic Carrier

3. Hydrophilic drug + Lipophilic carrier

4. Hydrophilic drug + Hydrophilic carrier

Is it possible for thermosensitive drug to

prepare SD by Solvent Evaporation

Method?

1. YES

2. NO

•Which method you’ll choose to select the carrier for

particular drug?

1. DSC and FT-IR

2. UV

3. XRD

4. NMR

Acknowledgment

I am very grateful to Dr. P.K.Deshmukh Sir for their invaluable

guidance.

I am also thankful to Mr.Abhijeet Pandey, Mr.Swapnil Patil,

Mr.Ramesh Chitalkar, Mr.Kunal Bacchao, Ms.Prachiti Patil,

Ms.Neha Chalase, Ms.Diksha Pagare for their kind help.

My Colleagues provided me direct and indirect help, I am also

thankful to them.

28

Health & Medicine

Enhancement of Solubility By Solid Dispersion- Presented By Mr.Ajinkya Nikam (National Award Winner Presentation)