Enhancement of the Solubility of Poorly Soluble Drug Substances Through the use of Formulation...

Enhancement of the Solubility of

Poorly Soluble Drug Substances

Through the use of Formulation

Additives

Harry G. Brittain

Center for Pharmaceutical Physics

10 Charles Road

Milford, NJ 08848

Factors that can Affect Solubility

• Nature of the drug substance

• Particle size

• Solvent system

• Solution pH

• Solubilizing agents

• Complexing agents

Nature of the Drug Substance

• Since the most stable crystal form under

defined conditions of temperature and

pressure has the lowest Gibbs free

energy, it must also have the lowest:

– Fugacity

– Vapor pressure

– Thermodynamic activity

– Solubility in any given solvent

– Intrinsic dissolution rate

Solubility of phenylbutazone in

various systems:

J. Pharm. Pharmacol., 35, 208-214 (1983)

Solubility of Polymorphs (mg/mL)

Solvent System I II IV V III

pH 7.5 phosphate buffer 4.80 5.10 5.15 5.35 5.9

above buffer with 0.05% Tween 80

4.50 4.85 4.95 5.10 5.52

above buffer with 2.25% PEG 300

3.52 5.77 5.85 6.15 6.72

Effect of Particle Size

• It has been known for a very long time (e.g., Noyes and Whitney, 1897) that the particle size of a dissolving solute affects its dissolution rate.

• Thermodynamics predicts that particle size should have no effect on solubility, and only a minor effect on the dissolution rate.

• However, experimental observations indicate that particle size can have a large effect on dissolution rate.

• Therefore, the phenomenon of dissolution rate enhancement must be associated with non-equilibrium situations.

Salicylic Acid dissolution rates

• Dissolution

profiles for

various mesh

sizes: 200/230

(), 120/140

( ), 60/80 (),

40/60 ( ), and

20/30 () mesh.

– J Pharm Sci

(1970) 59: 979-

984

Factors Affecting Dissolution Rates (1)

• Effect of stirring

rate (=50 rpm;

=100 rpm;

=125 rpm) on

the dissolution

profile of fluoro-

cortisone acetate.

– J. Pharm. Sci.,

67, 1397 (1978)


• Effect of medium

viscosity on the

dissolution rate of

benzoic acid in

sucrose solutions.

– J. Pharm. Sci.,

61, 175 (1972)


• Dissolution of

indomethacin

(), 2-naphthoic

acid (), and

benzoic acid

() as a

function of pH.

– J. Pharm. Sci.,

70, 13 (1981)


• Effect of polysorbate concentration on the dissolution of phenacetin.

– J. Pharm. Sci., 57, 1322 (1968)

What can be Formulated into a

Dosage Form to Enhance Solubility

• Nature of the drug substance: choose the most soluble form

• Particle size: use the finest particle size that can be handled without problems

• Acidifying/Basifying agents: include buffering agents in the formulation to modify dissolving environment

• Solubilizing agents: include surfactants to enhance solubility through solubilization

• Complexing agents: include interactive compounds that enhance solubility but which do not affect the pharmacological profile

Acetylsalicylic Acid Hydrolysis

• Acetylsalicylic acid (ASA) is prone toward hydrolysis, with the main decomposition product being salicylic acid.

• The hydrolysis reaction is known to be base-catalyzed, so basic excipients in a formulation cause excessive hydrolytic reactions.

• For example, the degree of degradation of ASA has been shown (among other things) to be a function of the quantity of magnesium stearate present in the formulation [W.J. Irwin et al, J. Pharm. Sci., 71, 1096 (1982)].

Solid-Phase Acidity and Hydrolysis (1)

• Using thymol blue as the adsorbed indicator, the surface acidity value for dicalcium phosphate anhydrate (DCP) was found to be 2.70

• Samples of the DCP were modified by treatment with a variety of buffer solutions, yielding solids that had a wide range of initial Ho values.

• ASA was dissolved in methanol, dried onto the surfaces of the different DCP materials, and these subjected to accelerated test conditions.

P.C. Schmidt et al, Eur. J. Pharm. Biopharm., 41, 114 (1995)

Solid-Phase Acidity and Hydrolysis (2)

• Decomposition of ASA at 30 C, 56% RH

P.C. Schmidt et al, Eur. J. Pharm. Biopharm., 41, 114 (1995)

Formulation to Control Acidity or

Basicity of Solids

• For drug substances demonstrated to prone toward hydrolytic reactions, it is important to determine whether the reaction is acid or base catalyzed.

• Excipients for such drug substances should be chosen on the basis of their relative solid-state acidities or basicities.

• One can use reflectance spectroscopy of adsorbed acid-base indicators to identify proposed excipients that have acceptable properties.

Effect of Polymers on Solubility

• Dissolution of carbamazepine (), and its solid dispersions formulated at drug/polymer ratios of 1:9 (), 3:7 ( ), and 6:4 ().

Polyethylene glycol 4000 Povidone (MW=49,000)

Int J Pharm (2002) 240: 11-22

Polyethylene glycols (1)

• General structure:

• Different molecular weight grades have different melting points

600 (MP = 15-25ºC) 1000 (MP = 35-40ºC)

1500 (MP = 42-48ºC) 3000 (MP = 50-56ºC)

4000 (MP = 53-59ºC) 6000 (MP = 55-61ºC)

8000 (MP = 55-62ºC)


• Solubilization of tenoxicam by PEG 4000 in a 1:3 drug/excipient coprecipitate:

Drug Dev Indust Pharm (2000) 26: 925-930

0 10 20 30 400

20

40

60

80

100

tenoxicam

PEG 4000

time (min)

Perc

en

t D

isso

lved


• The proper amount of solubilizing excipient in a coprecipitate product must be determined, and the use of too much may be counter-productive.

• Percent itraconazole dissolved in 100 minutes from PEG 20000 coprecipitates:

PEG/itraconazole (0:100) 14.6%




Pharm Res (2008) 25: 1274-1289


• The solubilization of naproxen by PEG is a function of the molecular weight of the excipient:



• The solubilization of naproxen by PEG is also a function of how the coprecipitate was prepared:



• An important consideration is whether the drug substance and PEG form a monotectic or eutectic composition:

Monotectic phase diagram, Eutectic phase diagram,

Formed by naproxen with PEG formed by fenofibrate and

flurbiprofen with PEG

• J Pharm Sci (2007) 96: 294-304

0 50 100

0 50 100

Vitamin E TPGS (1)

• d- -tocopheryl polyethylene glycol 1000 succinate:

• Melting point = 41ºC

• Hydrophile-lipophile balance = 15-19

Vitamin E TPGS (2)

• Surface tension of vitamin E TPGS in water:

Vitamin E TPGS (3)

• Solubilization of cyclosporine by vitamin E TPGS:

HG Brittain, unpublished results

0.0 0.1 0.2 0.3 0.4 0.50.00

0.05

0.10

0.15

0.20

0.25

Vitamin E TPGS (% w/w)

Cyc

losp

ori

n c

on

cen

trat

ion

(m

g/m

L)

Vitamin E TPGS (4)

• The solubilization of furosemide by vitamin E TPGS is also a function of how the formulation is prepared.

• This solid dispersion was prepared by evaporation of a methanol solution.

Int J Pharm (2003) 251: 79-84

Cyclodextrins (1)

• The family of

Cyclodextrins are

cyclic

oligosaccharides

derived from the

hydrolysis of

starch.

• Cyclodextrins are

composed of -

(1,4)-linkages of

D(+)-gluco

pyranose units.

Cyclodextrins (2)

• The interior of a cyclodextrin molecule is in

the shape of a conical cavity.

• The interior of the torus is hydrophobic, and

the exterior is hydrophilic, so cyclodextrins are

capable of binding molecules in the cavity and

causing their solubilization.

Cyclodextrins (3)

• -cyclodextrin consists of 6 glucose units in

the torus, -cyclodextrin contains 7 glucose

units, and -cyclodextrin contains 8 units.

Cyclodextrins (4)

• The number of glucose molecules

determines the properties of the cyclodextrin,

and its complexation tendencies.

Cyclodextrins (5)

• The binding strength of a compound with a cyclodextrin depends critically on the chemical structure of the included molecule.

Example is for -cyclodextrin [J Am Chem Soc (1977) 99: 5146-5151]

OH

NO2

OH

NO2

CH3

OH

NO2

CH3

OH

NO2

CH3 CH3

K = 5.3 K = 4.2 K = 0.18 No Binding

Cyclodextrins (6)

• Effect of different

cyclodextrins on

the solubility of

fluasterone.

– HP=hydroxypropyl

– SBE=sulfobutyl

ether

J Pharm Sci (1999) 88:

967-969

Cyclodextrins (7)

• While the method of formulation can affect the dissolution rate, it will not affect the equilibrium solubility of the inclusion complex.

• Dissolution of ibuprofen granules prepared by wet granulation ( ) and a physical mixture ().

J Pharm Sci (2003) 92: 1690-1697

Solubilization through Complexation

with Small Molecules (1)

• The formation of a molecular complex between a

drug substance and a suitable small molecule

can often lead to an enhancement in the solubility

of that drug substance.

• The small molecule can be formulated with the

drug substance.

• When the intermolecular interactions are

appropriate, the small molecule can be used to

modify the properties of the drug substance itself

(i.e., formation of a cocrystal).



• Complexation of nifedipine with phenolic compounds:

• Pharm Res (1988) 5: 655-659



• The ability of a complexing molecule to maintain

enhanced solubility requires maintenance of the

intermolecular interaction when the two

compounds are in the dissolved state.

• For example, benzoic acid is solubilized by

benzamide through formation of a dimer species:



• Dissolution profiles of fluoxetine/carboxylic acid cocrystals

• Drug Discovery Today (2008) 13: 440-446:

Summary

• Choose the most soluble form of the drug substance

– Free acid or base, or salt form?

– Polymorph, solvatomorph, or cocrystal?

• If no form of the API is entirely suitable, and particle size reduction does not suffice either, then use of a formulation additive should be considered.

– Acidifying, basifying, or buffering agents to modify the dissolution environment

– Solubilizing Agents to modify the dissolution environment through solubilization

– Complexing agents that associate with the API and carry the drug substance into solution

Enhancement of the Solubility of Poorly Soluble Drug Substances Through the use of Formulation...

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