19th Batch Part-2 Final Exam Routine

Date	Course Number	Time
2-1-12	PHR-201	9.00am-1.00pm
7-1-12	PHR-202	9.00am-1.00pm
12-1-12	PHR-203	9.00am-1.00pm
17-1-12	PHR-204	9.00am-1.00pm
22-1-12	PHR-205	9.00am-1.00pm
26-1-12	PHR-208	9.00am-12.00pm
31-1-12	PHR-209	9.00am-12.00pm
5-2-12	PHR-207	9.00am-1.00pm
11-2-12	PHR-206	9.00am-1.00pm

PREFORMULATION

                                 Preformulation

Some commonly evaluated parameters:

l Solubility

l Dissolution behavior

l Stability

l Partition coefficient

l Ionization constant (pKa)

l Solid state properties such as crystal forms/polymorphs, water sorption

behavior, surface properties, particle size and shape, and other mechanical

properties, et. al.

CONTENTS:-

I. PHYSICAL CHARACTERISTICS

A. BULK CHARACTERISTIC

1) Particle Size & Surface Area.

2) Polymorphism.

3) Crystallinity.

4) Hygroscopicity.

5) Flow properties & Bulk density.

6) Compressibility.

7) Drug-Excipient Compactibility.

8) Electrostatic charge.

9) Osmolarity.

10) Rheology.

11) Wettability.

B. SOLUBILITY ANALYSIS

1) Aqueous Solubility.

a) Intrinsic Solubility.

b) Dissociation Constant.

2) Solubilization.

3) Partition Coefficient.

4) Thermal effect.

5) Common ion effect.

6) Dissolution.

C. STABILITY ANALYSIS

1) Solid State Stability.

2) Solution State Stability.

II. CHEMICAL CHARACTERISTICS

1) Oxidation.

2) Hydrolysis.

3) Photolysis.

4) Racemization.

5) Polymerization.

6) Isomerization.

7) Decarboxylation.

8) Enzyme Decomposition.

q What Is PREFORMULATION?

It is defined as phase of research and development in which

preformulation scientist characterize physical & chemical properties of new

drug molecule in order to develop safe, effective, and stable dosage form.

DIRECT BENEFITS:

q Gives direction for development of formulation in choice of dosage

form,excipients,composition,physical structure.

q Helps in adjustment of Pharmacokinetics and biopharmaceutical properties.

q Support for process development of drug substance (yield,filtration..).

q Produce necessary and useful data for development of analytical methods

[B] SOLUBILITY ANALYSIS

AQUEOUS SOLUBILITY

A drug must possess aqueous solubility for therapeutic efficacy in physiological pH

range of 1 to 8 at 37 ºC.

Poor solubility (<10mg/ml) may result into bioabsorption problems.

If solubility of drug is less than 1 mg/ml it indicates the need for a salt, particularly if

the drug will be formulated as a tablet or capsule.

In the range 1-10 mg/ml serious consideration should be given to salt formation.

There are 2 fundamental properties mandatory for a new compd.

[a] Intrinsic Solubility (Co).

[b] Ionization Constant (pKa).

[a] INTRINSIC SOLUBILITY(Co):-

The solubility of weakly acidic & weakly basic drug as a function of pH can be

predicted with the help of eqn.

S = So {1 + (K1 / [H+])} -------------- for weak acids.

S = So {1 + ([H+] / K2)} -------------- for weak bases.

where, S = Solubility at given pH.

So = Intrinsic solubility of the neutral form.

K1 = Dissociation constant of weak acid.

K2 = Dissociation constant of weak base.

The intrinsic solubility should ideally be measured at 2 temperatures:

a) 4 ºC → To ensure physical & chemical stability.

b) 37 ºC → To support biopharmaceutical evaluation

[b] IONIZATION CONSTANT (pKa):-

75 % of all drugs are weak bases,

25 % are weak acids and only,

5 % are nonionic amphoteric or alcohol.

The unionized forms are more lipid soluble & more rapidly absorbed from g.i.t.

The relative conc. of unionized & ionized form of weakly acidic or basic drug in a

solution at a given pH can be calculated using the Henderson-Hasselbalch

equation:-

pH = pKa + log [unionized form] / [ionized form] ---- for weak bases.

pH = pKa + log [ionized form] / [unionized form] ---- for weak acids.

SOLUBILIZATION

Many different approaches have been developed to improve drug solubility:

1) Micronization:-

Eg. Griseofulvin shows increased solubility by reducing particle size.

2) Change in pH:-

Eg. Solubility of Nimesulide increases as pH is increased.

3) Cosolvency:-

Addition of a water miscible solvent can often improve the solubility of a weak

electrolyte or nonpolar compound in water by altering the polarity of the solvent.

The choice of suitable cosolvent is limited for P’ceutical use because of possible

toxicity & irritancy.

Ideally suitable blends should possess values of dielectric constant between 25-80.

Commonly used cosolvents are ethanol, sorbitol, glycerin, propylene glycol,

dimethylacetamide (DMA), DMSO, etc.

4) Solubilization by surfactant:-

Eg. Gelucire 44/14 is a surface active excipient that can solubilize poorly soluble drugs

5) Complexation:-

Eg. The Complexation of iodine with 10-15% polyvinylpyrolidone (PVP) can improve

aqueous solubility of active agent.

6) Formation of Inclusion Compound

PARTITION COEFFICIENT:-

§ The gastrointestinal membranes are largely lipoidal in character hence the lipid

solubility of a drug is an imp. factor in the assessment for its absorption potential.

§ When a solute is added to two immiscible liquids it will distribute itself between

the two phases in a fixed ratio, which is referred to as partition or distribution

coefficient.

§ It is independent of concentration of dilute solution of given solute species.

§ Various organic solvents used in determination of partition coefficient include

Chloroform, ether, amyl acetate, etc.

§ Solubility parameter of n-octanol (δ=10.24) lies midway in the range for major drugs

(δ=8-12). Thus in formulation development the n-octanol-water partition coefficient

is commonly used.

§ P= (Conc. of drug in octanol) / (Conc. of drug in water) --- For unionizable drugs.

§ P= (Conc. of drug in octanol) / (1-α)*(Conc. of drug in water) --- For ionizable drugs.

where α = degree of ionization.

§ P > 1 ð Lipophilic drug.

§ P < 1 ð Hydrophilic drug.

§ The value of P at which maximum activity of controlled release dosage forms is

observed is approximately 1000:1 in octanol/water

THERMAL EFFECT:-

§ Effect of temperature on the solubility of drug can be determined by measuring heat

of solution. (ΔHs).

ln S = -ΔHs/R*T + C.

COMMON ION EFFECT:-

Addition of common ion reduces the solubility of slightly soluble electrolyte.

The “salting out” results from the removal of water molecules as solvent due to the

competing hydration of other ions.

So weakly basic drug which are given as HCl salts have decreased solubility in acidic

solution.

Eg. Chlortetracycline, Papaverine, Bromhexine, Triamterene, etc.

The reverse process “salting in” arises with larger anions. (Eg. Benzoate, salicylate)

which can open the water structure.

These hydrotropes increase the solubility of poorly water soluble compounds.

To identify a common ion interaction the IDR (Intrinsic dissolution rate) of HCl salt

should be compared between

a) Water & water containing 1.2% W/V NaCl.

b) 0.05 M HCl & 0.9% NaCl in 0.05 M HCl.

Both saline media contains 0.2 M Cl which is typically encountered in fluids in vivo.

DISSOLUTION

§ The absorption of solid drugs administered orally can be understood by following

flowchart.

1.Dissolution Absorption

Solid drugs

in GI fluid

2.Drugs in systemic

circulation

3.Solution of drug

in GI fluid

STABILITY ANALYSIS

Development of a drug substance into a suitable dosage form requires the

Preformulation stability studies of drug under the following categories:-

[1] Solid state stability.

[2] Solution state stability

Solid state stability

Solid state reactions are much slower & more difficult to interpret than solution

state reactions because of reduced no. of molecular contacts between drug &

excipient molecules & occurrence of multiple reactions.

õ Techniques for solid state stability studies:

Solid State NMR Spectroscopy. (SSNMR)

Powder X-ray diffraction. (PXRD)

Fourier Transform IR. (FTIR)

Raman Spectroscopy.

Differential Scanning Calorimetry. (DSC).

Thermo gravimetric Analysis. (TGA).

Dynamic Vapor Sorption. (DSV).

[2]

Solution State Stability

The primary objective is identification of conditions necessary to form a solution.

These studies include the effects of

- pH. - Temperature.

- Light. - Oxygen. -

Cosolvent. - Ionic Strength

(1)  HYGROSCOPICITY

Hygroscopicity: - It is the tendency of material to absorb moisture

from atmosphere & get dynamic equilibrium with water in the

atmosphere.

1. PARTICLE SIZE & SIZE DISTRIBUTION :

If size (or) dimensions of particles altered

Particles shape changes

flow of particles changed

Ø Size distribution is carried out by using proper amounts of fines.

2. PARTICLE SHAPE & SURFACE MORPHOLOGY :

Ø Spherical shape is the best shape which give maximum flow.

Ø Irregular shape may cause bridging in hopper

Bulk density :-

¨ Bulk density of a compound varies substantially with the method of

crystallization, milling, or formulation.

¨ Bulk density measurement :The bulk density of a powder is

dependent on particle packing and changes as the powder

consolidates. A consolidated powder is likely to have a greater arch

strength than a less consolidated one and may therefore be more

resistant to powder flow. The ease with which a powder

consolidates can be used as an indirect method of quantifying

powder flow.

DEFINATION:-

Polymorphism: Elements can exist in two or more different forms, known as

allotropes of that element .eg.

Carbon: diamond in cubic (tetrahedral lattice arrangement)

graphite in sheets of a hexagonal lattice.

Similar phenomenon in compounds, scientifically referred to as polymorphism

The term polymorphism was coined by AGUIAR ETAL in 1967.

THUS IT IS DEFINED AS THE ABILITY OF SUBSTANCE TO EXIST AS TWO

OR MORE CRYSTALLINE PHASES THAT HAVE DIFFERENT

ARRRANGEMENTS OR CONFIRMATIONS OF THE MOLECULES IN THE  

CRYSTAL LATTICE.

PROPERTIES OF POLYMORPHS:-

Polymorphs show the same properties in liquid or gaseous state but they behave

differently in solid state.

Polymorphs differ from each other with respect to physical properties like

Melting and sublimation temperature

Vapour pressure

Solubility and dissolution rate

Stability

Optical and electrical properties

Crystal habit

Hygroscopicity

Heat capacity

Solid –state reactions

Conductivity

Compression characteristic

Thermal analysis

Definition:

Thermal method of analysis are group of techniques in which changes in

physical and /or chemical properties of a substance are measured as a function of

temperature, while substance is subjected to controlled temp programme

ROLE OF THERMAL ANALYSIS IN PREFORMULATION

1) They are unique methods in the field of polymer analysis & of high value for a

solid state analysis.

2) They finds wide application in

A) Detection of impurity

B) Determination of moisture content in any drug substance or any excipient

C) Study of polymorphism

D) Characterization of hydrates & solvates

E) Degree of Crystallinity

F) Study of phase diagram

G) Drug excipient compatibility study

H) Study of complexation

                                                                    

IFTAKHAR KHANDAKAR SHUKHON B’PHARM HONS 2ND  Year UNIVERSITY OF SCIENCE & TECHNOLOGY,CHITTAGONG ROLL:667