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 |
I would like to know more about this dissociation constant. Can you tell me more about this subject? I first came across with http://dissociationconstant.com/ and I'm currently looking for more details "outside the box".. you know what I mean.
ReplyDeleteAbstract: We will determine Ka and the molar mass for an unknown weak acid by using a pH meter to record the pH at intervals during the titration with sodium hydroxide. The titration curve and its first copied will be plotted to establish the equivalence point.
ReplyDeleteIntroduction
The power of an acid is defined by its ability to donate a proton to a base. For many common acids, we can quantify acid strength by expressing it as the equilibrium constant for the reaction in which the acid donates a proton to the standard base, water, as shown in the equations below:
HA + H2O Û H3O+ + A-,
for H3CCOOH:
H3CCOOH + H2O Û H3O+ + H3CCOO -
The equilibrium constant for a reaction of this type is called the Acid Dissociation Constant, "Ka", for the acid HA.
A convenient method for determining Ka is to measure the pH of a solution of the acid after a strong base has been added to half counterbalance it. We can calculate the amount in millimoles (mmol) of base added by multiplying the volume in mL by the concentration in mmol per mL, which is the same as the molar concentration (in moles per liter) since both the numerator and denominator are divided by 1000:
n(mmol) = V(mL) x C (mmol/mL)
For example, if 10 mL of 0.10 M NaOH is added to 20 mL of 0.10 M acetic acid, the solution will initially contain 10 mL x 0.10 mmol/mL = 1 mmol of NaOH, and 20 mL x 0.10 mmol/mL = 2 mmol of acetic acid.
OH- + H3CCOOH Û H2O + H3CCOO-
init 1 mmol 2 mmol
change -1 mmol -1 mmol +1 mmol
final 0 mmol 1 mmol +1 mmol
since the reaction goes essentially to completion, the 1 mmol of NaOH will be completely consumed, converting 1 mmol of acetic acid to acetate ion. Then [HA] = [A-] = 1 mmol/30 mL = 0.033 M. The Ka expression is simplified because identical terms cancel out:
=
Thus at the point of half-neutralization, Ka = [H3O+] or pKa = pH, where
pKa = - log Ka, just as
pH = - log [H3O+].
The Henderson-Hasselbalch equation,