chapter ii 2.1 literature on bioavailability and...

8

CHAPTER II

2.1 LITERATURE ON BIOAVAILABILITY AND

DISSOLUTION RATE

The most important property of a dosage form is its ability to deliver the

active ingredients to its site of action in an amount sufficient to elicit the desired

pharmacological response. This property of the dosage form has been variously

referred to as its physiological availability, biologic availability or bioavailability.

Bioavailability is defined more precisely as the rate and extent of absorption of a

drug from its dosage form into the systemic circulation. Accordingly, the absorption

of an intravenously administered drug is instantaneous and complete. However, for

reasons of convenience and stability, most drugs are administered orally after first

being formulated into dosage forms, usually tablets or capsules. The rate and extent

of absorption from such dosage forms is usually not precisely known as it is affected

by a number of factors related to the drug, dosage form and patient.

Dosage form related factors which can produce profound differences in drug

bioavailability include formulation and manufacturing variables such as, particle

size, the chemical form and solubility of the drug, the type and quantity of the

excipients used, the compaction pressure etc. Among the patient related factors those

over which the physician and/or the patient can exert some control include the time

of administration of the drug relative to meals, co-administration of other drugs

which may influence the absorption and compliance of the patient with the

instructions of the physician, pharmacist or nurse. The patient related factors which

9

normally cannot be controlled but for which some allowance (or) adjustment can be

made include age, disease state, abnormal genital characteristics and/or gastro-

intestinal physiology. The active ingredient in a solid dosage form must undergo

dissolution before it is available for absorption in the gastro-intestinal tract.

Dissolution forms the rate limiting step in the absorption of drugs from solid dosage

forms especially when the drug is poorly soluble.

Methods to enhance bioavailability can be related to one of two approaches.

The first is pharmaceutically dependent and involves improvement of the absorption

attributes by increasing the dissolution rate of the drug preparation. This usually is

achieved by changing certain ingredients in the formulation, optimizing the

manufacturing process or by altering the physico-chemical properties of the drug

substance without altering its molecular structure. The second approach is

pharmacokinetically dependent and deals with resolving specific bioavailability

problems that are intrinsic mainly to the drug chemical entity which includes, using

salt or ester form of the drug or prodrugs or by increasing the non-polar portion of a

molecule by extending the length of the chain. In certain cases, however, significant

enhancement of bioavailability can be obtained by modulating the drug metabolic

fate, its distribution characteristics or its excretion profile.

Dissolution and Absorption of Drugs from Solid Dosage Forms:

Before being absorbed into systemic circulation, drugs must dissolve in body

fluids existing at the site of absorption and the dissolved drug molecules from

solution absorb or cross the biological barriers by various drug transport

m

g

s

b

d

S

a

o

s

a

i

c

t

mechanisms

goes into s

solvent com

better related

Wag

dissolution o

Scheme -I i

administratio

only from th

small degree

and agglom

involves the

contents mu

then be tra

s. Dissolutio

olution per

mposition an

d to drug abs

gner1 propos

of solid dosa

indicates the

on in the for

he fine parti

e from intac

merates prod

e absorption

ust diffuse th

ansported th

on rate can b

unit time u

nd constant s

sorption and

ed the follo

age forms.

e processes

rm of a tabl

icles of the

ct dosage fo

duced after

n of the dru

hrough the a

hrough the b

10

be defined a

under stand

solid surfac

d bioavailabi

owing schem

Scheme -1

involved in

et or capsule

drug that ar

rm before it

disintegratio

ugs. The dru

aqueous fluid

barrier to t

as the amoun

dard conditio

e area. It is

ility.

me for the p

n the absorp

e. Dissolutio

re ultimately

ts disintegra

on. In vivo,

ug dissolved

ds to the gas

the systemic

nt of solid s

ons of temp

s a dynamic

processes inv

ption of dru

on of the dru

y produced,

ation and fro

process-4

d in the gas

stro intestina

c circulation

ubstance tha

perature, pH

c process an

volved in th

ugs after ora

ug occurs no

but also to

om fragment

(scheme - I

stro intestina

al barrier an

n. When th

at

H,

nd

he

al

ot

a

ts

I)

al

nd

he

11

dissolution process is very much slower than the other processes, then the

dissolution essentially and completely controls absorption rate. There is adequate

evidence now available to conclude that the dissolution rate often partially or totally

controls the rate of absorption. This is particularly true in the case of poorly soluble

drugs. Examples of drugs for which dissolution rate limited absorption was observed

include aspirin, tolbutamide, spiranolactone, prednisone, methyl prednisone,

ampicillin, griseofulvin, sulphamethiazine, salicylamide, etc. The rates of the

process of disintegration, deaggregation and dissolution are all dependent upon the

composition and method of preparation of the dosage form. These rates are all

largely dependent upon pharmaceutical factors, which the formulator can alter.

A more quantitative description of the dissolution rate is given by the Noyes-

Whitney2 equation based on diffusion layer model:

( )s

dc DS C C

dt h

Where

dc/dt - Rate of dissolution

S - Surface area

D - Diffusion coefficient

h - Thickness of the diffusion layer

Cs - Saturation solubility

C - Concentration of drug in solvent at time‘t’

12

In dissolution rate limited absorption C is negligible compared to Cs. Under

well defined conditions of use, D and h are relatively constant values that are not

conveniently altered to any degree by product formulation. Hence,

dc / dt = K ' S.CS

i.e. Dissolution rate α Surface area X Solubility

Thus, increasing either solubility or surface area or both can increase

dissolution rate of poorly soluble drug. These two variables can be altered by the

following techniques.

1. Controlling the solubility of weak acid or base by buffering either the entire

dissolution medium or the microenvironment i.e. the diffusion layer

surrounding a particle through the use of buffers and salts.

2. Controlling the solubility of the drug through the choice of physical state

such as crystal form, its hydrates, its amorphous form and so on.

3. Controlling the surface area of the drug through control of particle size.

Methods to Enhance the Dissolution Rate and Absorption of Poorly Soluble Drugs:

The different methods available to enhance the dissolution and absorption rates

of poorly soluble drugs are summarized in Table 2.1

13

Table 2.1

Methods to Enhance the Dissolution of Poorly Soluble Drugs

Method Examples of drugs investigated

I. Methods which increase the solubility

i. Buffering the pH of the

microenvironment

Buffered aspirin 3-5, theophylline6, sulfamethoxazole7 and

Cotrimoxazole8.Carvediol-hydroxypropyl-β-cyclodextrin61.

Telmisartan - hydroxypropyl-β-cyclodextrin62.

ii. Use of salts of weak acids

and weak bases

Na, K, Ca salts of p-aminosalicylic acid9, sod. tolbutamide10,

tetracycline HC111, Na and K salts of penicillin V12, sod.

phenobarbitone13, theophylline isoprenoline14 and choline

theophylline15.

iii. Use of solvates and

hydrates

Ampicillin anhydrate16, caffeine and glutethimide anhydrous

forms17, solvated forms of succinyl sulphathiazole and hydro

cortisone17.

iv. Use of selected

polymorphic forms

Novobiocin18, chloramphenicol palmitate19 and succinyl

sulphathiazole20,21.

v. Complexation Benzocaine-caffeine22, digitoxin-hydroquinone23, caffeine-ergot

alkaloids24, PVP54. Etoricoxib-β-cyclodextrin58. Celecoxib-β and

HPβ-cyclodextrin60.

vi. Prodrug approach Pivampicillin25, hectacillin26, erythromycin-21-N-alkylsuccinate27,

2'-N-alkyl glutaramate, prodrugs of carbenicillm28, lincomycin and

clindamycin29.

14

vii. Use of surfactants Hydrocortisone-Tween8030, amphotercin-B-biosurfactants31

(sod.taurocholate and sod.cholate), tolbutamide-Tween 20 and

Tween 8032, sulphathiazole, prednisolone and chloramphenicol -

polysorbate 8033.

viii. Sublimation Technique Etoricoxib-Menthol, Crospovidone55, Etoricoxib- camphor,

menthol, thymol, low substituted hydroxylpropyl methyl cellulose,

low substituted hydroxyl-propyl cellulose, croscarmellose sodium,

crospovidone, sodium starch glycolate56.

II. Methods which increase the surface area

1. Micronization (particle size

reduction to increase the

surface area)

Griseofulvin34,35, digoxin36,37, phenacetin38 and Sulphadiazine39

2. Use of surfactants (to

increase effective surface

area by facilitating proper

wetting)

Phenacetin40, ethinamate41, sulfisoxazole42

3. Solvent deposition

(deposition of poorly

soluble drugs on inert

materials)

Oxyphenbutazone43, prednisolone44, tolbutamide45, indomethacin46,

phenylbutazone47,48 and hydrochlorthiazide46.

4. Solid dispersions

(dispersion of poorly

soluble drug in a solid

matrix of water soluble

carrier)

Griseoflvin-PVP49, reserpine-PVP50, tolbutamide-PEG51 and

chloramphenicolurea52. Etoricoxib-croscarmellose sodium,

crosspovidone57. Aceclofenac-crosspovidone, PVP-K 3059

.

15

NEWER TECHNOLOGIES 63

Newer and novel drug delivery technologies developed in recent years for

bioavailability enhancement of insoluble drugs are listed below.

Lipid Based Delivery Systems:

Lipid Solutions,

Lipid Emulsions

Microemulsions

Self-Dispersing Lipid Formulations (SDLF)

Self-Emulsifying Drug Delivery Systems (SEDDS)

Self-Microemulsifying Drug Delivery Systems (SMEDDS)

Nanosizing by precipitation:

Evaporative Precipitation into Aqueous Solution (EPAS)

Controlled Precipitation

Cryogenic and Super critical fluid technologies.

Biopharmaceutical Classification System:

Biopharmaceutical Classification System53 (BCS) guidance was provided by

US Food and Drug Administration (FDA), to improve the efficiency of drug product

development process. According to which drugs are grouped into four major classes

basing on their solubility and permeability.

16

Class I: High Permeability and High Solubility

Propranolol, Metoprolol, Diltiazem, Verapamil

Class II: High Permeability and Low Solubility

Ketoconazole, Mefenamic acid, Nifedipine, Nicardipine, Felodipine,

Piroxicam, Celecoxib

Class III: Low permeability and High solubility

Acyclovir, Neomycin B, Captopril, Enalaprilate, Alendronate

Class IV: Low permeability and Low solubility

Chlorthiazide, Furosemide, Tobramycin, Cefuroxime

A drug substance is considered highly soluble when the highest dose strength

is soluble in < 250 ml water over a pH range of 1 to 7.5 and it is considered highly

permeable when the extent of absorption in humans is determined to be > 90% of an

administered dose, based on mass-balance or in comparison to an intravenous

reference dose. A drug product is considered to be rapidly dissolving when > 85% of

the labeled amount of drug substance dissolves within 30 minutes using USP

apparatus I or II in a volume of < 900 ml buffer solutions.

The rate limiting process for drug absorption and bioavailability (rate and

extent of absorption) is either the release (or dissolution) of drug substances from the

dosage form or its permeation through the intestinal membrane. If permeation

through intestinal membrane is rate limiting, dissolution properties may be of

negligible importance. Class I drugs behave in vivo like an oral solution. Dissolution

and bioavailability is very rapid for these drugs. If the Class I drug substance is

17

released from the dosage form very rapidly in vivo, gastric emptying will become

the rate limiting process for drug absorption. Whereas for drugs having high

permeability and low solubility (Class II), dissolution or release from the dosage

form occurs slowly and the dissolution rate will become the rate limiting factor for

drug absorption. These drugs exhibit variable bioavailability and need enhancement

in dissolution rate for increasing bioavailability. Permeation through the intestinal

membrane forms the rate-limiting step for absorption of drugs of Class III and

bioavailability is independent of drug release from the dosage form. These drugs

generally exhibit low bioavailability and need enhancement in permeability. Class

IV drugs exhibit poor and variable bioavailability. Several factors such as

dissolution rate, permeability, gastric emptying form rate limiting steps for

absorption of these drugs.

18

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3. Leonards JR. Clin. Pharmacol. Ther., 1963; 4:476.

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6. Nelson E. J.Pharm. Sci., 1958; 47: 300.

7. Chowdary KPR, Ravi Kumar T. Indian J.Pharm. Sci., 1983; 45: 228.

8. Chowdary KPR, Srirama Murtrhy A. Indian Drugs. 1985; 22: 538.

9. Wan SH, Pentikainen PJ, Azarnoff DL. J.Pharm. Sci., 1974; 63: 708.

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12. Juncher H, Raaschov F. Antibiot. Med. Clin. Ther., 1957; 4: 497.

13. Nelson E. J.Amer. Pharm. Assoc. Sci. Ed., 1958; 47: 297.

14. Vivino EA. 0.1N hydrochloric acid, 1954; 43: 234.

15. Gagliani De, Graff AC, Kupperman HS. Int. Rec. Med. Gen. Prac.Clin., 1954;

167:251.

16. Poole JW, Owen G, Silvero J, Freyhot JN, Roseman SB. Curr. Ther. Res., 1968;

10: 292.

17. Shefter E, Higuchi T. J. Amer. Pharm. Assoc., 1958; 47: 297.

18. Mullins JD, Macek TJ. J. Amer. Pharm. Assoc., 1958; 47: 297.

19. Aguiar AJ, Krc J, Kinkel AW Samyn JC. J. Pharm. Sci., 1967; 56: 847.

20. Moustafa MA, Khalil SA, Ebian AR, Motawi MM. J. Pharm. Sci., 1974; 63: 1103.

19

21. Moustafa MA, Khalil SA, Ebian AR, Motawi MM. J. Pharm. Sci., 1975; 64:

1481.

22. Higuchi WI, Nir NA, Desai SJ. J. Pharm. Sci., 1965; 54: 1405.

23. Higuchi T, Ikeda M. J. Pharm. Sci, 1974; 63: 809.

24. Zoglio MA, Maulding HV, Windheuser J. J. Pharm. Sci., 1969; 58: 222.

25. Daehne WV, Frederiksen E, Gundersen E, Lund F, Morch P, Peterson HJ, Roholt

K, Tybring L, Godtfredsen WO. J. Med. Chem., 1970; 13: 607.

26. Schwartz MA, Hayton WL. J. Pharm. Sci., 1972; 61: 906.

27. Sinkula AA, Acta Pharm. Suec., 1976; 13: 7.

28. Butter K, English AR, Knirsch AK, Korst JJ. Del. Med. J., 1971; 43: 366.

29. Sinkula AA, Lewis C. J. Pharma. Sci., 1973; 62: 1757.

30. Hazratwala BR, Taylor B. J. Pharma. Pharmacol, 1974; 28: 934.

31. Goyal VC, Kohil DV, Upadhyay RK, Indian Drugs. 1982; 19: 233.

32. Sanghvi NM, Jirani NJ, Indian Drugs. 1982; 19: 421.

33. Chiou WL, Chen SJ, Athanikar N. J. Pharm. Sci., 1976; 65: 1702.

34. Bedford C, Busfield D, Child KJ, Mac Gregor J, Sutherland P, Tomich E G. Arch.

Dermantol., 1960; 81: 735.

35. Atkinson R, Bedford C, Child KJ, Tomich EG. Nature (Lond.), 1962; 193: 588.

36. Shaw TRD, Careless JE. Eur. J. Clin. Pharmacol., 1974; 7: 269.

37. Jounela AJ, Pentikainen PJ, Sothmann A. Eur. J. Clin. Pharmacol., 1975; 8: 365.

38. Finholt P, Dissolution Technology (Leeson LJ, Carstensen JT. Eds.) Academy of

Pharmaceutical Sciences, American Pharmaceutical Association. Washington

D.C., 1974, p. 106-146.

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39. Reinhold JG, Phillips FJ, Flippin HF. Amer. J. Med. Sci., 1945; 210: 141.

40. Finholt P, Solvang S. J. Pharma. Sci., 1968; 57:1322.

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42. Kakemi K, Arita T, Muranishi S. Chem. Pharm. Bull., 1965; 13: 976.

43. Jain SC, Agrawal GP. Indian Drugs. 1981; 19: 108.

44. Narurkar AN, Jarowski CI. Drug Dev. Ind. Pharm., 1983; 9: 999.

45. Mortada LM, Mortada SAM. Acta Pharm. Tech., 1982; 28: 297.

46. Monkhouse DC, Lach JL. J. Pharm. Sci., 1972; 61: 1430.

47. Johansen H, Moeller N. Arch. Pharm. Chem. Sci. Ed., 1976; 4:114.

48. Johansen H, Moeller N. Arch. Pharm. Chem. Sci. Ed., 1977; 5: 171.

49. Mayersohn M, Gibaldi M. J. Pharm. Sci., 1966; 55:1323.

50. Stupak EI, Bates TR. J. Pharma. Sci., 1972; 61: 400.

51. Kaur R, Grant DJW, Eaves T. J. Pharm. Sci., 1980; 69: 1317.

52. Sekiguchi K, Obi N. Ueda Y. Chem. Pharm. Bull., 1964; 12: 134.

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Evaluation and Research, US Food and Drug Administration, 2001,

http://www.fda.gov/cder.

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55. Patel DM, Patel MM. Ind.J. Pharm. Sci., 2008; 71.

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224:32.

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60. Chowdary KPR, Lingaraj S.Danki. Int.J.Chem.Sci, 2008; 887.

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22

2.2 LITERATURE ON CYCLODEXTRIN COMPLEXATION

Cyclodextrins (CDs), homologous cyclic oligosaccharides have long been

known to increase the apparent solubility of many lipophilic drugs through non-

covalent inclusion complexation1, 2. Cyclodextrins and their derivatives play an

important role in the formulation development due to their effect on solubility,

dissolution rate, chemical stability and absorption of a drug.3, 4

The α-, β- and γ- cyclodextrins are cyclic oligosaccharides consisting of six,

seven and eight glucose units respectively. While it is thought that, due to steric

factors, Cyclodextrins having fewer than six glucopyranose units cannot exist,

Cyclodextrins containing nine, ten, eleven, twelve and thirteen glucopyranose units,

which are designated δ-, ε-, ζ-, η, and δ-cyclodextrin, respectively, have been

reported5,6 of these large-ring Cyclodextrins only β-cyclodextrin has been well

characterized7,8. Chemical and physical properties of the four most common

Cyclodextrins are given in Table 2.2. The melting points of α-, β- and γ -

cyclodextrins are between 240° and 265°C, consistent with their stable crystal lattice

structure9.

c

h

a

o

No.

Centr

Water so

They

cyclodextrin

hydrolysed s

acyclic dext

of the most i

The

Some Char

of glucopyra

Molecular w

ral cavity dia

olubility at 2

y are enz

n-glucosyl t

starch (a mix

trins, from w

important CD

Fig

'torus' shap

racteristics

anose units

weight

ameter (A°)

5°C (g/100 m

zymatic co

transferase

xture of line

which pure c

D, β-cyclode

g. 2.1: The S

ped macro-r

23

Table 2.2

of α -, β -, γ

9

4.7

ml) 1

nversion p

produced b

ar dextrins)

cyclodextrin

extrin is sho

Structure of

ring is buil

- and δ –Cy

α

6

972 1

7-5.3 6.

14.5 1

products of

by B. mace

and produce

ns (CDs) are

wn in Fig-2

f β -cyclodex

lt of α-l, 4

yclodextrin

β

7

1135 1

0-6.5 7.5

1.85 2

f starch. T

erans acts

es a mixture

e isolated10.

.1.

xtrin

4-D-glucose

s

γ

8

297

5-8.3 10

23.2

The enzym

on partiall

of cyclic an

The structur

units. As

δ

9

1459

0.3-11.2

8.19

me

ly

nd

re

a

24

consequence of conformation of glucopyranose units, all secondary OH- groups are

located on one edge (wider edge) of the 'torus' like CD molecule while all primary

OH-groups are on the other side (narrow side of torus). The lining of the internal

cavity is formed by OH-atoms and glucosidic oxygen-bridge atoms, therefore, the

inner surface is hydrophobic, but outer surface is hydrophilic.

Absorption and Toxicity:

Cyclodextrins are not absorbed orally and not hydrolyzed during their transit

through the small intestine. They are totally resistant to α-amylases, but can be

attacked by β-amylases. Hydrolysis occurs only in colon (partial hydrolysis occurs

with α-CD). The oral administration of CDs does not result in acute toxicity. Long

term administration leads to no significant change in organs or biological values.

Natural CDs are highly toxic when given parenterally. α- and β-cyclodextrins induce

haemolysis and nephrotoxicity upon i.v. injection γ CD is relatively less toxic

parenterally11.

Formation of Complexes:

One of the most important characteristics of CDs are their ability to form

inclusion complexes. Inclusion complexation involves entrapment of a guest

molecule totally or partially in the cavity of host molecule without formation of any

covalent bonds. CDs are typical host molecules and can entrap a wide variety of

drug molecules resulting in the formation of monomolecular inclusion complexes12.

Inclusion complexation occurs when aqueous solution of CD is shaken with

drug molecules or its solution. In aqueous solution the hydrophobic cavities of CD

25

are occupied by water molecules, which can be replaced by appropriate drug

molecules that are less polar than water. The solubility of the complex is usually

lesser than the solubility of CD and hence the complex maybe precipitated from its

saturated solution, as microcrystalline powder and this powder is subsequently

separated by filteration13. Usually 1:1 complexes are formed, but when a guest

molecule is too long to find complete accommodation in one cavity, its other end is

also amenable to complex formation leading to 2:1 (CD : drug) or sometimes 3:1 or

4:1 complexes. It may also be possible to form 1:2 and 1:3 (CD: drug) complexes.

The central cavity of the cyclodextrin molecule is linked with skeletal

carbons and ethereal oxygens of the glucose residues. It is therefore lipophilic. The

polarity of the cavity has been estimated to be similar to that of aqueous ethanolic

solution14. It provides a lipophilic microenvironment into which suitably sized drug

molecules may enter and be included. No covalent bonds are formed or broken

during drug-cyclodextrin complex formation, and in aqueous solutions, the

complexes are readily dissociated. Free drug molecules are in equilibrium with the

molecules bound within the cyclodextrin cavity Measurements of stability or

equilibrium constants (Kc) or the dissociation constants (Kd) of the drug-

cyclodextrin complexes are important properties of a compound upon inclusion.

Methods for Detection of Inclusion Complex Formation and Determination of

Complex Stability Constant:

One of the most interesting properties of CDs is their ability to form

inclusion complexes with a wide variety of guest molecules. Molecular

encapsulation may occur both in solution and solid state. In solution there is

26

equilibrium between complexed and non complexed guest molecules, in solid state

guest molecules can be enclosed within the cavity or may be aggregated to the

outside of CD molecule15. Upon inclusion within the CD cavity a guest molecule

experiences changes in its physicochemical properties. These changes provide

methods to detect whether guest molecules are really included in the CD cavity.

Detection of inclusion complexation in the solution state:

Detection of inclusion complexation in solution state can be done by

spectroscopic methods like Ultraviolet/Visible (UV/VIS), Fluorescence, Circular

Dichroism, Electron Spin Resonance (ESR), and Nuclear Magnetic Resonance

(NMR) methods. The 1H-NMR and 13C-NMR spectroscopic studies can also be used

to determine the direction of penetration of guest molecules in to the CD cavity.

Other methods include Polarography, Conductivity measurement, Microcalorimetry

and Solubility methods2.

Phase solubility technique16 is the one of the widely used methods to detect

the inclusion complexation in solution state.

The general experimental operation in studying molecular interactions by

means of phase solubility method entails the addition of an equal weight

(inconsiderable excess of its normal solubility) of a slightly soluble compound, S

(substrate or guest) into each of several vials containing increasing concentrations of

a relatively soluble compound, L (ligand or host or complex agent), which are closed

and brought to solubility equilibrium at constant temperature. The solution phases

are then analyzed, by any suitable means, for their total concentration of compound

S

c

t

g

t

f

t

c

i

c

t

r

a

S (guest), no

A ph

concentratio

The

type B with

The

guest solubi

those of the

from the stra

type diagram

cyclodextrin

interaction m

contribution

type, the ini

region and t

accompanyin

o matter wha

hase diagram

on of S found

phase diagr

some variati

type A can

lity of first t

e second and

aight line. T

m, where as

n molecules

mechanism

n of solute-so

itial ascendin

then a decre

ng a microc

at its molecu

m is construc

d in the solut

ams are obs

ion within th

be further c

type increase

d third types

The complex

the higher o

are involve

for the AN

olvent intera

ng portion o

ease in the

crystalline pr

27

ular state may

cted by plott

tion phase ag

served to fal

he classes.

classified in

es linearly w

s deviate po

formation w

order comple

ed in the co

N-type is co

action to the

of the solubi

solubility a

recipitation o

y be.

ting, on the

gainst the m

ll into two m

subtypes A

with cyclode

ositively and

with a 1:1 st

ex formation

omplexation

mplicated, b

e complexati

ility change

at higher cyc

of the comp

vertical axi

molar concent

main classes

AL, AP and A

xtrin concen

d negatively,

oichiometry

n in which m

n gives the A

because of

ion. In the c

is followed

clodextrin c

lex. The BI-

s, total mola

tration of L.

s, type A an

AN, where th

ntration whil

, respectivel

y gives the A

more than on

AP-type. Th

a significan

ase of the B

d by a platea

oncentration

-type diagram

ar

nd

he

le

ly

AL

ne

he

nt

Bs

au

ns

m

28

is indicative of the formation of insoluble complexes in water.

The stability constant (Ks) and stoichiometry of complexes are determined by

analyzing quantitatively the phase solubility diagram.

Detection of inclusion complexation in the solid state:

Detection of the inclusion complexation in solid state can be done by Powder

X-ray diffractometry, Single crystal X-ray structure analysis, Thermo analytical, thin

layer chromatography, Paper chromatography, Infrared spectroscopy, Scanning

electron microscopy and Dissolution study methods2.

Applications of Cyclodextrins:

All the applications of CDs in drug formulations involve complexation11,17-19.

When a drug becomes part of a CD complex, its physical and chemical properties

are modified20. The solubility and dissolution rate of drugs are improved in CD

complexes; poorly soluble drugs reach the blood more quickly and in higher

concentration, suggesting the possibility of reducing the dose21.

β-CD is most widely used for complexation because of its unique cavity size

and ease with which it can be obtained on industrial scale, leading to reasonably

cheaper price of this compound22.

β-Cyclodextrin complex formation with lipophilic drugs and other

compounds with limited aqueous solubility, frequently gives rise to B-type phase-

solubility diagrams as defined by Higuchi16. β-and δ-cyclodextrin form

intramolecular hydrogen bonds between secondary OH groups, which detract from

29

hydrogen bond formation with surrounding water molecules, resulting in less

negative heats of hydration8, 14. Thus, intramolecular hydrogen bonding can result in

relatively unfavourable enthalpies of solution and low aqueous solubilities. For

example, the aqueous solubility of β-cyclodextrin is only 1.85% w/v at room

temperature but increases with increasing degree of methylation. The highest

solubility is obtained when two-thirds of the hydroxyl groups (i.e., 14 of 21) are

methylated, but then falls upon more complete alkylation. The methylated derivative

has a solubility that is lower than that of e.g., heptakis (2, 6-o-dimethyl)-β-

cyclodextrin but that is still considerably higher than that of unsubstituted β-

cyclodextrin23.

Recent Research Work on Cyclodextrin Complexation:

Several studies reported the cyclodextrin complexation of a variety of drugs

for various purposes. A summary of recent research work on cyclodextrin

complexation for enhancing the dissolution rate and bioavailability is given in Table

2.3.

30

Table 2.3

Summary of Recent Research Work on Cyclodextrin Complexation

S. No.

Drug Cyclodextrin (CD) Purpose/Result Ref.No.

1. Acetaminophen α- and β -cyclodextrins Effect of humidity on inclusion complex formation and their characterization by XRD, DSC and IR are reported

24

2. Albendazole α-, β- and HPβCD Improved solubility and dissolution rate

25

3. Amlodipine β- and HPβCD Improved solubility and characterization of inclusion complexes by DSC and thermogravimetric methods

26

4. Benzthiazide β-, γ- and Dimethyl βCD Increased dissolution rate and inclusion complexes in solution and solid state were prepared and characterized by IR and DSC

27

5. Bromozepam Dimethyl βCD Characterization of inclusion complexes by IR, XRD and DSC techniques

28

6. Broperimine β CD Improved dissolution rate and stability studies

29

7. Butyl methoxy dibenzoyl methiane (Sunscreen agent)

α-, β -,γ- and HPβCD Characterization by phase solubility analysis, circular dichroism, DSC and XRD studies and improved solubility and photostability of complexes are reported

30

8. Chenodeoxycholic acid

β-and Dimethyl- βCD Improved aqueous solubility and dissolution rate

31

31

9. Clotrimazole Dimethyl- βCD Improved aqueous solubility, dissolution rate and antimycotic activity

32

10. Danazol HPβCD and sulfobutyl ether of β-cyclodextrin

Improved aqueous solubility and dissolution rate

33

11. Diclobutrazol α-,β-,Dimethyl β-and HPβCD

Improved aqueous solubility and dissolution rate

34

12. Felodipine β-and HPβCD Improved solubility and characterization of inclusion complexes by DSC and thermogravimetric methods

26

13. Fenabufen α-, β - and γ-cyclodextrins Improved dissolution rate and oral bioavailability of inclusion complexes

35

14. Fucosterol β-, Maltosyl- β- and Dimethyl- β CD

Improved solubility, dissolution rate and stoichiometry and stability constants were reported

36

15. Furosemide Cyclodextrins Improved solubility and dissolution rate

37

16. Glibenclamide β - HP β and Dimethyl- βCD

Improved dissolution rate 38

17. Glisentide α-, β - and γCD Complexation in aqueous solution and solid state is investigated

39

18 Griseofulvin β- and HPβCD Improved dissolution rate 40

19. Ibuprofen β-Methy,l β-HP, and Hydroxyethyl β CD


20 Indomethacin β- and HPβCD The methods of preparation of inclusion complexes and their characterization in liquid and solid phases were reported

42

21. Indomethacin β- and HPβCD Decreased G.I irritation 43

32

22. Indomethacin α-, β- and γCD Enhanced solubility and phase solubility studies were reported

44

23. Insulin α-, β-, γ-HPβ and Dimethyl βCD

Enhanced pulmonary absorption

45

24. Ketoconazole β- and HPβCD Phase solubility studies and improved dissolution of complexes prepared by spray drying and kneading methods were reported

46

25. Ketoprofen α-, β-, HPβ and Dimethyl βCD

Improved dissolution rate and bioavailability

47

26. Ketoprofen β-Methyl β-, HPβ- and Hydroxyethyl βCD


27. Meclizine HC1 α-, β- and γCD Improved dissolution rate 48

28 Menadione βCD Increased stability, solubility and decreased skin irritation were reported

49

29. Mesalamine α- and βCD Physical characterization by XRD, SEM, DSC and mass spectrometry

50

30. Miconazole HPβCD Crystallinity was investigated in solid complexes

51

31. Miconazole α-, β-, γ- Methyl β-, HP β- and Hydroxyethyl βCD

Improved solubility, skin retention and oral bioavailability

52

32. Naproxen βCD Improved dissolution rate of complexes and their characterization by XRD and DSC were reported

53

33. Norfloxacin β-and HPβCD Improved dissolution rate 54

34. Oxazepam Dimethyl βCD Improved dissolution rate and complex formation in solution by solubility. UV spectroscopy methods , DSC, XRD and SEM techniques were reported

55

33

35. Psoralen βCD Improved dissolution rates

56

36. Spironolactone α-, β- and γCD Improved aqueous solubility of inclusion complexes and phase solubility studies were reported

57

37. Spironolactone Cyclodextrins Improved dissolution rate by direct compression was reported

58

38. Spironolactone α-, β-, HPβ- and HPβCD Improved dissolution and bioavailability

59

39. Temazepam β- and HPβCD Improved dissolution rate 60

40. Terfenadine α- and βCD Improved dissolution rate 61

41. Tolbutamide βCD Improved dissolution and phase solubility studies were reported

62

42. Tolbutamide βCD Improved absorption and bioavailability were reported

63

43. Tolnaftate β- and HPβCD Increased solubility and dissolution rate

64

44. Tretinoin Dimethyl βCD Increased solubility 65

45. Urodeoxycholic acid

β- and Dimethyl βCD Increased solubility and dissolution rate

31

46 Anandamine HPβCD Increased solubility and stability

66

47. Ampicillin β-CD Increased solubility, dissolution rate and bioavailability

67

48. Allopurinol β-CD Increased solubility, dissolution rate

67

49. Paracetamol β-CD Increased solubility 68

50. Ibuprofin α-, β - and γCD Increased solubility, dissolution rate was increased

69

34

51. Mebandazole α,β-,γ-,and HPβCD Improved solubility and characterization of inclusion complex formation by phase solubility

70

52. Nimesulide βCD and L-lysine Increased solubility and dissolution rate

71

53. Nimesulide HPβCD and βCD increased solubility and dissolution rate

72

54.

Leteprednol etabonate

γ-,HPβCD, Maltosyl-β- and Dimethyl-βCD

Higher solubility and stability was observed in Dimethyl- βCD than HPβCD

73

55. Tolbutamide βCD improved dissolution by presence of CD and surfactant

74

56 Omeprazole γCD Improved dissolution rate prepared by coprecipitation method

75

57. Gliclazide βCD Improved dissolution rate 76

58 Nimesulide βCD Higher rates of dissolution and dissolution efficiency

77

59. Ofloxacin βCD Enhanced solubility, but not photostabilization

78

60. Piroxicam HPβCD Increased permeation and release of drug from the gel

79

61. Sulfamethiazole βCD, HPβCD Improved dissolution rate 80

62. Ciprofloxacin βCD Conformation of existence of inclusion complexation

81

63. Bromazepam βCD, HPβCD Enhanced solubility 82

64. Furosemide HPβCD Characterization of inclusion complexes by DSC and XRD

83

35

65. Nifedipine βCD, HPβCD and DMβCD Enhanced solubility and photo stability and Characterization of inclusion complexes by DSC, XRD and IR

84

66. Nicardipine HC1

Triacetyl βCD In vitro release was markedly retarded ;

85

67. Nicardipine βCD, HPβCD Enhanced dissolution rate 86

68. Natamycin βCD, γCD, HPβCD Enhanced dissolution rate 87

69 Nimodipine

βCD, HPβCD and

HEβCD, MβCD, αCD, HPαCD,

MβCD was found as efficient

solubilizer and HPβCD as a good solubiliser

88

70. β-lapachone α-, β-, γ- and HPβCD improved solubility and bioavailability, complex formation proved by 1H-NMR and fluorescence spectroscopy

89

71. Ciprofloxacin HPβCD Better stability, biological activity and ocular tolerance was observed

90

72. Nifedipine β-CD Enhanced solubility and dissolution rate

91

73. Isoproturon β-CD Improved dissolution rate 92

74 Artemisinin α -, β- and γ- CD Enhanced solubility and dissolution rate

93

75. Acitretin HPβCD and RMβCD Enhanced solubility and photostability. Characterization of inclusion complexes by IR, DSC, XRD

94

76. Nimesulide α -, β- and γ- CD Enhanced solubility and photostability. Characterization of inclusion complexes by IR, DSC, XRD

95

77. Carbamazepine β-CD Improvement in release rate

96

36

78. Furosemide HPβCD Preparation and characterization of inclusion complexes by phase solubility studies, DSC, NMR improvement in solubility and dissolution rate

97

79. Dehydroepiandro-sterone

αCD Improved dissolution rate, solubility and bioavailability

98

80 Nicardipine β-cyclodextrin Critical combination of cyclodextrin offered prolonged therapeutic activity.

99

81 Triflumizole β-CD Increased dissolution rate 100

82 Nitrendipine HPβCD Complexes showed better dissolution rates 101

83 Nimesulide β -cyclodextrin Enhancement of drug dissolution rate.

102

84. Carbamazepine SBE-βCD Solubility of drug increased

103

85 Azadirachtin βCD/DMβCD/ permethylβCD/ HPβCD

Dissolution properties for superior compared to pure drug

104

86. Celecoxib DMβCD Exhibited higher rate of dissolution

105

87 Quinlukast αCD/βCD/HPβCD/MEβCD Complexes showed better

dissolution rates

106

88 Lorazepam

HPβCD/ HPγCD/

SBE-βCD/ MEβCD

Improved dissolution rates

and bioavailability

107

89 Fenoxaprop-p-

ethyl

βCD/ HPβCD/

RMβCD

Improved dissolution rates

and bioavailability

108

90 Diazepam

HPβCD/ HPγCD/

SBE- βCD/

MEβCD

Dissolution rate was

markedly increased

109

37

91 Diclofenac sodium

β cyclodextrin Drug dissolution rate was improved in presence of cyclodextrins.

110

92 Azelaic aicd HP-β cyclodextrin Release rate of azelaic acid through the synthetic membranes were enhanced

111

93 Melasoprol β-cyclodextrin, Methylated-β cyclodextrin, HP-β cyclodextrin

Complexes had a pronounced effect on drug hydrolysis and dissolution rate.

112

94 Ethyleneoxide β cyclodextrin Enhancement of dissolution rate

113

95 Piribedil Cyclodextrin

Dissolution profile was improved too great extent.

114

96 Glimpiride β cyclodextrin, HP- β cyclodextrin

Great enhancement in dissolution rate, increased duration of action and improvement of therapeutic efficacy of drug.

115

97 Glyburide β cyclodextrin, HP- β cyclodextrin

Dissolution profile was improved significantly.

116

98 Efavirenz β cyclodextrin, HP- β cyclodextrin

Great enhancement in dissolution rate

117

99 Benzophenone Cyclodextrin For the preparation of Nanogels

118

100 Cilostazol β cyclodextrin, HP- β cyclodextrin

Improved dissolution rates and bioavailability.

119

101 Flurbiprofen β cyclodextrin Improved bioavailability. 120

102 Flurbiprofen Cyclodextrin Improved bioavailability. 121

103 Aceclofenac β cyclodextrin, HP- β cyclodextrin

Improved water solubility and in vitro dissolution rate.

122

104 Amoxicillin β cyclodextrin Improved water solubility and interactions

123

105 Curcumin HP-γ-cyclodextrin Improved dissolution and bioavailability

124

38

106 Repaglinide β cyclodextrin, HP-β cyclodextrin and methylated β cyclodextrin

Improved solubility 125

107 Praziquantel β cyclodextrin Improved bioavailability 126

108 Melarsoprol HP-β-cyclodextrin and randomly methylated β-CD


109 Narigenin β cyclodextrin and HP-β cyclodextrin


110 Pioglitazone Methylated β cyclodextrin Improved solubility 129

111 Aspirin β cyclodextrin Improved solubility 130

112 Sufenatil 2-HP- β-cyclodextrin Improved solubility

131

113 Nitrazepam HP- β-CD and sulfobutyl ether β-CD

Improved solubility and bioavailability

132

114 Promethazine β-cyclodextrin Improved bioavailability 133

115 Piroxicam β cyclodextrin and HP- β-cyclodextrin


39

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123. Catherine Bisson-Boutelliez, Stephane Fontanay, Chantal Finance,

Francine Kedziereiez. AAPS. Pharm.Sci.Tech., 2010; 11(2):574-581.

124. Vivek RV, Sahdeo P, Ramaswamy K, Jayraj R, Madan M.C, Lauri V,

Jaako P, Bharat BA. J.Biochem Pharmacol., 2010; 80: 1021-1032.

125. Camelia N, Corina A, Angela N, Crina-Maria M. Farmacia. 2010; 58:5.

126. De jesus MB, Pinto Lde M, Fraceto LF, Magalhaes LA, Zanotti-Magalahaes

EM, De Paula E. J.Drug Target., 2010; 18(1):21-6.

127. Jean R, Amy J, Stephane G, Barbara B, Christopher M, Michael P. B,

George G. PLOS Negl Tropo Dis. 2011; 5(9): 1308.

128. Maria S, Merav M, Hiroshi Y, Jonathan G, Martin L. PLOS ONE. 2011;

6(4):18033.

129. Pandit V, Gorantla R, Devi K, Pai R.S, Sarasija S. J.young

Pharmacists. Pharmaceutics. 2011; 3(4):267-274.

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130. Imran S, Vishal G, Abhay J, Naveen G. Int. J. Pharma. Life Sci., 2011;

2(4):704-710.

131. Cristiane V, Fabiana Y, Angelica F.A, Giorana R. J.Pharm Sci.,

2012; 101(10):3698-3707.

132. Patel JS, Patel RP. J. of Pharmacy and Allied Sci., 2010; 4(5):105-107.

133. Octavian P, Aurelia G. Cellulose Chem. Technol., 2012; 46(5-6):295-300.

134. Utra Kumar A, Pramella R. Int. J.Pharm. Phytopharmacol. Res., 2012;

1(5):301-305.

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2.3 SOLID DISPERSION TECHNOLOGIES

The term solid dispersion refers1 to a group of solid products consisting of at

least two different components, generally a hydrophilic matrix and a hydrophobic

drug. The matrix can be either crystalline or amorphous. The drug can be dispersed

molecularly, in amorphous particles (clusters) or in crystalline particles.

Advantages of solid dispersions

1. Particles with reduced particle size

Molecular dispersions, as solid dispersions, represent the last state on particle

size reduction, and after carrier dissolution the drug is molecularly dispersed in the

dissolution medium. Solid dispersions apply this principle to drug release by

creating a mixture of a poorly water soluble drug and highly soluble carriers2. A

high surface area is formed, resulting in an increased dissolution rate and,

consequently, improved bioavailability 2, 3.

2. Particles with improved wettability

A strong contribution to the enhancement of drug solubility is related to the

drug wettability improvement verified in solid dispersions4. It was observed that

even carriers without any surface activity, such as urea5 improved drug wettability.

Carriers with surface activity, such as cholic acid and bile salts when used, can

significantly increase the wettability of drug particles. Moreover, carriers can

influence the drug dissolution profile by direct dissolution or co-solvent effects. 6, 3

49

3. Particles with higher porosity

Particles in solid dispersions have been found to have a higher degree of

porosity7. The increase in porosity also depends on the carrier properties; for

instance, solid dispersions containing linear polymers produce larger and more

porous particles than those containing reticular polymers and, therefore, result in a

higher dissolution rate8. The increased porosity of solid dispersion particles also

hastens the drug release profile.

4. Drugs in amorphous state

Poorly water soluble crystalline drugs, when in the amorphous state tend to

have higher solubility 9, 10. The enhancement of drug release can usually be achieved

using the drug in its amorphous state, because no energy is required to break up the

crystal lattice during the dissolution process11. In solid dispersions, drugs are

presented as supersaturated solutions after system dissolution, and it is speculated

that, if drugs precipitate, it is as a metastable polymorphic form with higher

solubility than the most stable crystal form.2, 4 For drugs with low crystal energy

(low melting temperature or heat of fusion), the amorphous composition is primarily

dictated by the difference in melting temperature between drug and carrier. For

drugs with high crystal energy, higher amorphous compositions can be obtained by

choosing carriers, which exhibit specific interactions with them. 12

Properties of a Carrier for Solid Dispersions

Following criteria should be considered during selection of carriers: (a) High

water solubility – improve wettability and enhance dissolution (b) High glass

50

transition point – improve stability (c) Minimal water uptake (reduces Tg) (d)

Soluble in common solvent with drug –solvent evaporation (e) Relatively low

melting point –melting process (f) Capable of forming a solid solution with the drug-

similar solubility parameters .

First generation carriers

Crystalline carriers: Urea, Sugars, Organic acids

Second generation carriers

Amorphous carriers: Polyethyleneglycol, Povidone, Polyvinylacetate,

Polymethacrylate, cellulose derivatives

Third generation carriers

Surface active self emulsifying carriers: Poloxamer 408, Tween 80, Gelucire 44/14.

Solid dispersions of a number of poorly soluble drugs such as

phenylbutazone13, ketoprofen14, sulphathiazole15 etc. exhibited faster dissolution

rates and improved bioavailability. For example, a marked increase (30 fold) in

dissolution rate of indomethacin was observed with indomethacin-hydroxy propyl

cellulose solid dispersions. Indomethacin was present in amorphous form in these

dispersions. A significant increase in absorption rate and serum levels of

indomethacin was also observed with these dispersions.,

Solvent Deposition Systems

A solvent deposition (SD) system is defined as a solid preparation in which a

drug is deposited from its solution in a volatile solvent on the surface of an excipient

by evaporation of the solvent used for the distribution of the drug. Solvent

deposition can be used for two purposes, (i) to improve the dissolution rate and

51

efficiency and (ii) to achieve content uniformity.

Solvent deposition technique achieves faster dissolution rates as the drug

undergoes molecular micronization while depositing over the surface of the

excipient. The form 'miniscular form' is used to describe this state. The choice of the

support excipient has varied from very fine powder to granules, the former

obviously allows for a large surface for deposition, ensuring faster dissolution rates.

Solvent deposition may also lead to change in crystal type of the drug

(polymorphism). The polymorph of significantly greater thermodynamic activity

(i.e. solubility) can prove helpful in improving dissolution rate. Solvent deposition

may also convert a crystalline drug into amorphous form, which produces faster

dissolution and absorption rates.

Finely divided solids as well as granular support materials have been used for

preparing the SD systems. Finely divided solids perform very well when increased

dissolution rates are intended as they offer a large surface area, but content

uniformity may suffer because of difficulties like poor flow properties and clumping

which can lead to variable die-filling during capsule or tablet manufacturing.

Granular support materials offer additional advantage of excellent control over the

content uniformity and also they can be directly compressed after solvent deposition.

Other factors to be considered in the selection of excipient include solubility in

water and other solvents, compatibility with drugs, biologic inertness,

hygroscopicity and cost.

Materials such as silicagel 16, 17, macrocrystalline cellulose16-18, lactose16-19,

DCP16-17, silicon dioxide20-21, kaolin16, potato starch16, sucrose pellets22, lactose-

52

starch granules23, sodium starch glycolate24 and modified cellulose24 were reported

as excipients for solvent deposition systems.

Solvent deposited systems of a number of poorly soluble drugs such as

diazepam25, phenylbutazone13, piroxicam17, ketoprofen16, indomethacin26, digoxin19

exhibited faster dissolution rates and efficiency. For example, solvent deposited

systems of ketoprofen16 on silicagel, MCC, lactose, starch and DCP showed a

marked increase in the dissolution rate of ketoprofen. In a study17, it was noticed that

water insoluble excipients (MCC, silicagel, kaolin) gave fast dissolution when

compared to water soluble excipients (soluble starch, lactose) which themselves

dissolved leaving aggregates of the drug. The relatively fast dissolution observed

with water insoluble excipients may be due to the easy and rapid dispersible nature

of these materials giving more surface area.

53

REFFERENCES

1. Chiou WL and Riegelman S. J. Pharm. Sci., 1971; 60 (9): 1281-1302.

2. Leuner C and Dressman J. Eur. J. Pharm. Biopharm., 2000; 50: 47-60.

3. Kang BK, J S Lee, SK, Chon SY, Jeong S H and Yuk G. Int. J. Pharm., 2004;

274: 65-73.

4. Karavas E, Ktistis G, Xenakis A and Georgarakis E. Eur. J. Pharm.

Biopharm., 2006; 63: 103-114.

5. Sekiguchi K and Obi N. Chem. Pharm. Bull., (Tokyo), 1964; 12: 134-144.

6. Pouton C W. Eur. J. Pharm. Sci., 2006; 29: 278-287.

7. Vasconcelos T and Costa P. In: PSWC – Pharmaceutical Sciences World

Conference. DD-W. 2007; 103.

8. Ghaderi R, Artursson P and Carifors. J. Pharm. Res., 1999; 16: 676-681.

9. Pokharkar VB, Leenata P, Mandpe, Mahesh N, Padamwar, Anshuman A,

Ambike, Kakasaheb R, Mahadik, Anant, Paradkar. Powder Technol., 2006;

167: 20-25.

10. Lloyd G R, Craig DQ and Smith A. Eur. J. Pharm. Biopharm., 1999; 48: 59-

65.

11. Taylor L S and Zografi G. Pharm. Res., 1997; 14: 1691-1698.

12. Vippagunta S R, Karin A, Maul, Siva, Tallavajhala, David J W, Grant. Int. J.

Pharm., 2002;236(1-2): 111-123.

13. Krenschmen K, Forming KH and Hoseman R. Acta Pharm. Tech.,1980;

26:159.

14. Takayana K, Nambu N and Nakai T, Chem. Pharm. Bull., 1982; 30,

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15. Simonelli AP, Metra SC and Higuchi WI. J. Pharm. Sci., 1969; 58: 32.

16. Chowdary KPR and Madhusudan P. Indian J. Pharm. Sci., 1990; 52: 32.

17. Chowdary KPR and Ramakrishna S. Indian J. Pharm. Sci., 1990; 52: 269.

18. Sarabia R and Attias de Galidex, Expo. Congr. Int. Technol. Pharm., 1983;

5:231.

19. Amplonsk C. et al, J. Pharm. Sci., 1974; 63: 117.

20. Johansen H and Moelar N. Arch. Pharm. Chem. Sci., Ed., 1977; 33.

21. Martoda LM, Martoda, SAM. Arch. Pharm. Technol., 1982; 28:297.

22. Bansal AK and Kakkar AP. Ind. J. Pharm. Sci., 1978; 67: 134.

23. Johansen H and Moelar N. J. Pharm. Sci., 1978; 67:134.

24. Law SL and Chiang CH. Drug Dev. Ind. Pharm., 1990; 16: 137,

25. Japan Kakai. 77, 015 (CIA 61K 9/1), Appl. 1977; 75:102.

26. Monkhouse DC and Lach JL. J. Pharm. Sci., 1972; 61:1430.

chapter ii 2.1 literature on bioavailability and...

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