university of sulaimani college of pharmacy dept. of ...• for soluble compounds the rate of...

University of Sulaimani College of Pharmacy

Dept. of Pharmaceutics5th stage – First Semester

11/29/2019 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 1


Outlines

• Introduction

• Bulk characterization

• Solubility analysis

• Ionization constant pKa

• Thermal effect

• Solubilization

• Stability analysis


Solubility analysis

• Preformulation solubility studies focus on drug-solvent systems that could

occur during the delivery of a drug candidate.

• Analytical methods that are particularly useful for solubility measurements

include HPLC, UV spectroscopy, fluorescence spectroscopy, and gas

chromatography.

• Solubility profile are not predictors of biologic performance!


Solubility analysis

• Many drugs are either weak acids or weak bases.

• In solutions of these drugs, equilibria exist between undissociated

molecules and their ions.

• For acids

• HA ↔ H+ + A-

• For base

• H+ + B- ↔ BH

• Ionization constants of both acidic and basic drugs are usually expressed in

terms of pKa.

• 𝑝𝐾𝑎 = − log𝐾𝑎


Ionization constant pKa

• Determination of the dissociation constant is important since solubility,

and consequently absorption, can be altered with changing pH.

• pKa could be measured with UV, visible spectroscopy or potentiometric

titration.


Ionization constant pKa


Link between pKa, pH and ionization

• The degree of ionization is controlled by the pKa of the molecule and the

pH of its surrounding environment.

• For acidic compounds

• pH = p𝐾𝑎 + log𝑖𝑜𝑛𝑖𝑧𝑒𝑑

𝑢𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑

• For basic compounds

• pH = p𝐾𝑎 + log𝑢𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑

𝑖𝑜𝑛𝑖𝑧𝑒𝑑

• pKa for acidic drug such as

Acetylsalicylic acid = 3.5 and for

theophylline = 9

• pKa for basic drug such as caffeine =

0.8 and for atropine = 9.7


Partition coefficient logP

• For insoluble compounds the dissolution rate is often the rate determining

step in the overall absorption process.

• The dissolution rate can be changed by modifying the physicochemical

properties of the drug and/ or altering the formulation composition

• For soluble compounds the rate of permeation across biological

membranes is the rate determining step.

• The permeation rate is dependent upon the size, relative aqueous and

lipid solubility and ionic charge of drug molecules.



• For weak acid or weak base,

pH and lipid solubility of the

unionized species are

dominating factors for

absorption.

• Barbitone and thiopentone have similar pKa (7.8 vs 7.6) and therefore

similar degrees of ionization at intestinal pH.

• Thiopentone is absorbed much better than barbitone?



• Partition coefficient: is a measure of drug’s lipophilicity and it expressed as

logP

• 𝒑𝒂𝒓𝒕𝒊𝒕𝒊𝒐𝒏 𝒄𝒐𝒆𝒇𝒇𝒊𝒄𝒊𝒆𝒏𝒕 =𝒅𝒓𝒖𝒈 𝒄𝒐𝒏𝒄.𝒊𝒏 𝒐𝒓𝒈𝒂𝒏𝒊𝒄 𝒑𝒉𝒂𝒔𝒆

𝒅𝒓𝒖𝒈 𝒄𝒐𝒏𝒄.𝒊𝒏 𝒂𝒒𝒖𝒆𝒐𝒖𝒔 𝒑𝒉𝒂𝒔𝒆

• Polar molecule → logP < 0

• Gentamicin, ceftriaxone, heparin low oral absorption due to low logP

• Prodrug such as pivamicillin → to ampicillin and enalapril → enalaprilat


Outlines

• Introduction




• Thermal effect

• Solubilization



Thermal effect

• The heat of solution, ΔHs, represents the heat released or absorbed when

a mole of solute is dissolved in a large quantity of solvent.

• The higher the heat of solution, the greater the influence of temperature

on solubility.

• Commonly, the solution process is endothermic, or ΔHs is positive.

• Some hydrochloride salts are exothermic process.


Thermal effect cont.

• Heats of solution are determined from

solubility value for saturated solution

equilibrated at temperature 5 °C to 50 °C.

• 𝑙𝑛𝑆 =−ΔHs

𝑅

1

𝑇+ 𝐶

• S is the molar solubility

• Salt forms of drugs are often less sensitive

to temperature and may have heats of

solution between -2 and 2 kal/mole.So

lub

ility

of

eto

xad

rol,

mg

/mL

1/T (kelvin) * 10 -3

HCl saltΔHs = 2.1 kcal/mole

Free baseΔHs = 15.4 kcal/mole


Outlines

• Introduction




• Thermal effect

• Solubilization



BCS

• According to BCS, a large number of drug candidates do not make it to

the market because of poor bioavailability, primarily due to their poor

solubility in aqueous medium.

• pH, salt formation, cocrystals, prodrug, and cosolvency are among

methods for increasing solubility of poorly soluble drugs.

Class I

High solubility

High permeability

Class II

Low solubility

High permeability

Class III

High solubility

Low permeability

Class IV

Low solubility

Low permeability

High

Low

High LowSolubility

Perm

eab

ilit

y


BCS continue


Solubilization

• Determination of solubility

• The pH-solubility profile of the test drug should be determined at 37±1oC

in aqueous media with a pH in the rate of 1-7.5.

• Either traditional shake flask or acid-base titration methods can be used.

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

strength is soluble in 250 ml or less of aqueous media over the pH range of

1-7.5.

• A drug is considered to be highly permeable when

the extent of absorption in humans is ≥ 90% of an

administered dose in comparison to an intravenous

reference dose


Dissolution

• Dissolution is the process by which a solid enters into solution.

• When the dissolution rate is the rate-limiting step, anything that affects

it will also affect absorption.

• Noyes-Whitney equation was developed to define the dissolution from a

single spherical particle.

•𝑑𝑚

𝑑𝑡=

𝐷𝐴(𝐶𝑠−𝐶)

ℎ


Strategies to increase solubility

Strategies to increase solubility of poorly soluble drug

Particle size reduction

Mechanical

1. Jet milling

2. Ball milling

3. High pressure homogenization

Engineered control

Cryogenic spray

Other technologies

Cosolvent

Complexation

Surfactant

Solid dispersion


Particle size reduction

• Smaller the particle size, larger the surface area, and better the solubility.

• Reduction of particle size below 1 μm is suitable to improve the solubility.

• It is commonly used method for increasing solubility of BCS class II

drugs.

• Nanoparticles could be obtained by:

• Bottom-up technologies

• Top-down technologies

70 µm


Cryogenic spray process

• An aqueous or organic solution

or suspension containing a drug

and excipients are directly

atomized into a compressed gas

(such as CO2, helium, propane,

ethane) or the cryogenic liquids

(such as nitrogen, argon)

• SFL is an efficient method to

produce nanostructured particles

with amorphous structure and

high surface area.

Spray freezing into cryogenic liquids (SFL)


Cosolvent

• A cosolvent system is one in which a

water miscible or partially miscible organic

solvent is mixed with water.

• Cosolvents have some degree of hydrogen

bond donating and or hydrogen bond

accepting ability as well as small

hydrocarbon regions.

• It is an effective method to increase the

solubility of a non-polar drug.

• Examples like ethanol, propylene glycol, and

glycerin.

Hydrocortisone

Hydrocortisone 21 heptanoate


Complexation

• Complexation is the association between two or more molecules to form

a non-bonded entity with a well-defined stoichiometry.

• An inclusion complex is the inclusion of a nonpolar molecule (guest) into

the nonpolar cavity of another molecule (host).

• The most commonly used host molecules are the cyclodextrins. These

cyclic oligomers of glucose are relatively soluble in water.


Complexation

• Cyclodextrins contain 6, 7, and 8 glucopyranose units and are termed α, β,

and γ, respectively.

• Hydroxypropyl-b-cyclodextrin, HP-b-CD and the sulfobutylethers of b-

cyclodextrin, SBE-b-CD are very soluble in water.


Surfactant

• Surfactants are molecules with distinct polar and non-polar regions.

• Most surfactants consist of a hydrocarbon segment connected to a polar

group.

• The polar group can be:

• Anionic such as a carboxylate, sulfate, or sulfonate

• Cationic such as ammonium, or pyridinium

• Zwitterionic such as phosphatidylcholine (lecithin)

• Nonionic such as PEG, tween and span.


Surfactant cont.

• The concentration at which micelle begin to form is called the critical

micelle concentration (or the CMC).

• The polysorbate non-ionics have been employed in the preparation of

aqueous injections of the water-insoluble vitamins A, D, E and K.


SEDDS

• Self‐emulsifying drug delivery systems (SEDDSs) are mixture of oils and

surfactants, sometime contain co-surfactant/cosolvent, which emulsify and

produce oil-in-water emulsion when introduced into an aqueous phase.

• S-SEDDS focus on the incorporation of

liquid/semisolid SE ingredient into

powder/nanoparticles.

• The prepared mixture filled into capsule or

compressed to form tablet.SEDDS

Cosolvent

coSAA

Oils

Drug

SAA


Solid dispersion

• It is the dispersion of one or more active ingredients in an inert carrier or

matrix at solid state prepared by the melting, solvent, or melting–

solvent method.

• Dispersions obtained through the fusion process are often called melts.

• Those obtained by the solvent method are frequently referred to as

coprecipitates or coevaporates.


Solid dispersion cont.

A. Melting or Fusion Method

• A physical mixture of an active agent and a water–soluble carrier is heated

until it is melted.

• The melt is solidified rapidly in an ice bath under vigorous stirring,

pulverizing and then sieving.


Solid dispersion cont.

B. Solvent method

• The solvent is usually removed by evaporation under reduced pressure

at varying temperatures.

• The freeze–drying process has been used


Outlines

• Introduction





Shelf-life

• Stability of a pharmaceutical product is the capability of a particular formulation,

in a specific container/closure system, to remain within its physical, chemical,

microbiological, therapeutic, and toxicological specifications at a defined

storage condition.

• Shelf-life is the time in which a drug product in a specific packaging will remain

stable when stored under recommended conditions.

• 90% of labeled potency generally is recognized as the minimum acceptable

potency level over the shelf life of a drug product.


Expiration date

• Drug's potency begins to reduce from the moment it is manufactured; it is

not in any way spontaneous after the expiry date.

• Expired medications have not necessarily lost potency. The expiration date

is only an assurance that the labeled potency will last at least until that

time.

• Anticonvulsants, warfarin, digoxin → narrow therapeutic index

• Phenobarbital, theophylline, epinephrine and insulin → very quickly

lose potency

• Thyroid preparations and oral contraceptives

• Eye drops - eyes are particularly sensitive to any bacteria that might

grow in a solution once a preservative degrades.

• Do NOT try to increase the dose of expired drug!


Expiration date cont.

• OTC drugs without dosage limitations (e.g., antiperspirants, antidandruff

shampoos, toothpastes, sunscreens, etc.), do not require an expiration

date.

• Period after opening (POA) time

• That is, the time in months when the product will remain in good

condition after the consumer has used the product for the first time.

• Lifespan is more than 30 months

• Best before end date (BBE)

• Lifespan is less than 30 months


Pharmaceutically important temperatures

• Dry Place – denotes a place that does not exceed 40% average relative

humidity (RH) at controlled room temperature.

Pharmaceutically important temperatures

Description Temperature (°C)

Ultracold freezerFreezerFreezing point of waterRefrigeratorRoom temperature Boiling point of waterAutoclave

-70-2005

20-25100120


Stability testing and estimating the shelf life

• Stability testing shall be used to determine appropriate storage

conditions and expiration date.

• Stability protocols according to ICH.

• Time-related chemical stability failure:

• Decrease in therapeutic activity of the preparation to below some

labeled content.

• The appearance of a toxic substance, formed as a degradation product

upon storage of the formulation.


Estimation of the shelf life

• The pharmaceutical industry uses the Arrhenius plot, a graph of log k versus

the reciprocal of temperature to determine the shelf life for drugs

• Log K = log𝐴 +𝐸𝑎

2.303𝑅𝑇

40 °C

50 °C

60 °C

70 °C

2

1

Time, h

Dec

om

po

siti

on

, lo

g%

1/T * 10-3

Log

K

70 °C60 °C

50 °C

40 °C

2.9 3.1 3.3

Log K at room T


Stability analysis cont.

• Q10 method: is the ratio of two rate constants for a drug measured at two

temperatures that are 10 ˚C apart.

• An antibiotic solution has a shelf life of 48 hours at (5 °C). What is its

estimated shelf life at (35 °C)?

• 𝑄10∆𝑇/10

= 330/10 = 33 = 27

• T90T2=48

27= 1.7 h

𝑄∆𝑇 = 𝑇90𝑇1

𝑇90𝑇2

𝑄∆𝑇 = 𝑄10∆𝑇/10

Activation energy Ea (calories/mol)

kT2/kT1

K (Q10)

12.219.424.5

234

university of sulaimani college of pharmacy dept. of ...• for soluble compounds the rate of...

Documents