1.Concept of preformulation
2.Steps in preformulation process
7.pH- solubility profile
THE CONCEPT OF PREFORMULATION:-
Almost all drugs are marketed as tablets, capsules or both. Prior to the development of
these major dosage forms, it is essential that certain fundamental, physical and
chemical properties of the drug molecule and other properties of the drug powder are
determined. This information decides many of the subsequent events and approaches in
This first learning phase is known as preformulation
It can be defined as an investigation of physical and chemical properties of a drug
substance - alone and or when combined with excipients.
The overall objective of preformulation testing is to generate information useful to the
formulator in developing stable and safe dosage forms with good bioavailability.
During the early development of a new drug substance, the synthetic
chemist, alone or in cooperation with specialists in other disciplines
(including preformulation), may record some data which can be
appropriately considered as preformulation data.
This early data collection may include such information as
- Gross particle size,
- Melting point,
- Infrared analysis,
- Thin-layer chromatographic purity,
- And other characteristics .
These data are useful in guiding, and becoming part of, the main body of
1. Stability i. Solubility
a. Solid State (1) Water and Other Solvents
(2) pH-Solubility Profile
(3) Salt Forms
(4) Co solvents
b. Solution (5) Complexation
(1) Solvent (6) Prodrug
(2) pH j. partition coefficient
(3) Light k. polymorphism potential
3. Physico-mechanical Properties
a. Bulk and Tapped Density
a. Molecular Structure and Weight
d. Particle size, Shape, and Crystallinity
e. Melting Point 4. In Vitro Availability Properties
f. Thermal Analysis Profile a. Dissolution of Drug Crystal Per sec
(1) DTA b. Dissolution of Pure Drug Pellet
(2) DSC c. Dissolution Analysis of Pure Drug
g. Hygroscopicity Potential 5. Other Studies
h. Absorbance Spectra a. Plasma Protein Binding
(1) UV b. Effect of Compatible Excipients
(2) IR on Dissolution
Particle Size, Shape and Surface Area:-
Various chemical and physical properties of drug substances are affected by
their particle size distribution and shapes .The effect is not only on the physical
properties of solid drugs but also, in some instances, on their biopharmaceutical
behavior .It is generally recognized that poorly soluble drugs showing a
dissolution- rate limiting step in the absorption process will be more readily
bio available when administered in a finely subdivided state rather than as a
In case of tablets, size and shape influence the flow and the mixing efficiency of
powders and granules.
Size can also be a factor in stability .
Fine materials are relatively more open to attack from atmospheric oxygen,
the humidity, and interacting excipient than are coarse materials.
Effects of particle size and shape on:
- Chemical and physical properties of drug substances.
- Bioavailability of drug substances(Griseofulvin,Chlorpropamide).
- Flow and mixing efficiency of powders and granules in making
- Stability, fine materials relatively more open to attack from
atmospheric O2, heat, light, humidity, and interacting excipients
than coarse materials.
Very fine materials are difficult to handle, overcome by creating solid solution in a
carrier (water-soluble polymer).
Important to decide, maintain, and control a desired size range.
Safest - grind most new drugs with particle diameter > 100 mm (~ 140 mesh) down
to ~ 10 - 40 mm (~ 325 mesh).
Particles with diameter < 30 mm (~ 400 mesh), grinding is unnecessary except
needle-like to……. improve flow.
Drawbacks to grinding:
- Material losses.
- Static charge build-up.
- Aggregation => Lowering dissolution rate.
- Polymorphic or chemical transformations.
General Techniques For Determining Particle Size
- Most rapid technique.
- But for quantitative size determination requires counting large number of particles.
- Suspending the material in non dissolving fluid (water or mineral oil)
Particle size and shape can be determined by using optical microscope , polarizing
microscope or by scanning electron microscope (SEM).The data recorded either by a sketch
or more accurately by a photomicrograph .
Polarizing microscope is used to determine whether a compound is crystalline or
Crystalline structures are visible (Refract the polarized light). Amorphous are invisible
Crystal habit and internal structure of a drug can affect bulk and
physicochemical properties , which range from flowability to stability .
Habit is the description of the outer appearance of the crystal where as
internal structure is the molecular arrangement with in the solid .
Crystal habit types :
Tabular : moderate expansion of two parallel faces ;
Platy : excessive plate like development ;
Prismatic : columnar form ;
Acicular : needle like structure ;
Bladed : flattened acicular .
In internal structure of a compound the major distinction is whether the solid is
crystalline or amorphous .
Common Crystal Habits
HabitHabit DescriptionDescription ExampleExample
slender(very narrow),slender(very narrow),
and/or taperedand/or tapered
BladedBladed Blade-like, slender, andBlade-like, slender, and
ColumnarColumnar Similar to fibrous: long,Similar to fibrous: long,
slender prisms oftenslender prisms often
parallel growthparallel growth
Fibrous or columnarFibrous or columnar Extremely slenderExtremely slender
Filiform or capillaryFiliform or capillary Hair-like or thread-like,Hair-like or thread-like,
extremely fineextremely fine
GranularGranular Aggregates of anhedralAggregates of anhedral
crystals in matrixcrystals in matrix
PrismaticPrismatic Elongate, prism-like: allElongate, prism-like: all
crystal faces parallel tocrystal faces parallel to
MELTING POINT :-
Defined as the temperature at which the solid and liquid phases are in equilibrium .
the melting point of a drug can be measured using three techniques:-
1) Capillary melting
2) Hot stage microscopy
3) Differential scanning calorimetric or thermal analysis.
Capillary melting :-
Capillary melting gives information about the melting range but it is different to assign
an accurate melting point.
Hot stage microscopy:-
This the visual observation of melting under a microscope equipped with a heated and
lagged sample stage. The heating rate is controllable and up to three transitions can be
registered. These values are more accurate .
Differential scanning calorimetric and thermal analysis :-
Differential thermal analysis (DTA) measures the temperature difference between the
sample and a reference as a function of temperature or time when heating at a constant
Differential scanning calorimetric (DSC) is similar to DTA except that the instrument
measures the amount of energy required to keep the sample at the same temperature as12
THERMAL ANALYTICAL PROFILE :
Differential Scanning Calorimetry (DSC) and
Differential Thermal Analysis (DTA) measure the heat loss or gain
resulting from physical or chemical changes within a sample as a function
of temperature .
Examples of endothermic ( heat absorbing) process are.
Solid solid transitions and
chemical degradation .
exothermic process are crystallization ,degradation .
DSC thermograms of
pure acyclovir and pure
DSC thermograms of
containing 12.8 %
15 % propylene glycol
and 10 % Tween 80
Many drug substances , particularly water soluble salt forms have a tendency to
adsorb atmospheric moisture .
adsorption can depend upon the humidity
mechanism for moisture uptake .
The changes in moisture level can greatly influence many important parameters ,
such as chemical stability , flow ability and compatibility .
To carry out a study , samples are accurately weighed in a tarred containers and
placed at various humidity conditions for periods up to 2 weeks. Weight gain or
loss is measured at predetermined time intervals until equilibrium is reached .
If the drug is very hygroscopic or unstable in the presence of moisture , the drug
would have to be stored under dry conditions .
High hygroscopicity is undesirable for many reasons, including Handling problems,
requirement of special storage conditions, chemical and physical stability problems.
The solubility of drug is an important physicochemical property because it
affects the bioavailability of the drug, the rate of drug release into dissolution medium
and consequently, the therapeutic efficiency of the pharmaceutical product.
The solubility of the molecules in various solvents is determined as a first step.
This information is valuable in developing a formulation.
Solubility is usually determined in variety of commonly used solvents and some oils if
the molecules are lipophillic.
The solubility of material is usually determined by the equilibrium solubility method,
which employs a saturated solution of the material, obtained by stirring an excess of
material in the solvent for a prolonged until equilibrium achieved
Solubility > 1 % w/v
=> no dissolution-related absorption problem
The United States Pharmacopeia Solubility Classification
Descriptive term Parts of solvent required for
one part of solute
Very soluble Less than 1
Freely soluble From 1 to 10
Soluble From 10 to 30
Sparingly soluble From 30 to 100
Slightly soluble From 100 to1000
Very slightly soluble From 1000 to10,000
Practically insoluble or insoluble 10,000 and over
Common solvents used for solubility determination are:-
Water ,Polyethylene Glycols ,Propylene Glycol ,Glycerin ,Sorbitol
Ethyl Alcohol ,Methanol ,Benzyl Alcohol ,Isopropyl Alcohol ,Tweens
·Peanut Oil oils
·Buffer at various pHs
Adding solute in small
solute particles ?
Determination of Solubility…
Excess drug powder
150 mg/ml (15 %)
Shaking at constant
(25 or 37 o
(2 - 8 o
The first few ml’s of the filtrates should be
discarded due to possible filter adsorption 48 hr
Determine the drug
concentration in the
Determine the drug
concentration in the
Determine the drug
concentration in the
Accurately Quantitative determination:
Determination of the dissociation constant for a drug capable of ionization
within a pH range of 1 to 10 is important since solubility and consequently
absorption, can be altered by orders of magnitude with changing pH.
The Henderson – Hasselbalch equation provides an estimate of the ionized and
un ionized drug concentration at a particular pH.
For acidic compounds
pH= pKa + log(ionized drug)/(un ionized drug)
For basic compounds
pH = pKa + log (un-ionized drug]) / [ionized drug])
For a weakly acidic drug with pKa value greater than 3 , the un ionized form is
present within the acidic contents of the stomach , but the drug is ionized in the
neutral media of the intestine .
For basic drugs such as erythromycin and papaverine pKa 8-9 the ionized form
predominant in both the stomach and intestine .
Buffer ,temperature , ionic strength and co solvent affect the pKa value . 20
Partition Coefficient :-
Partition Coefficient (oil/ water) is a measure of a drug’s Lipophillicity and an
indication of its ability to cross cell membranes.
It is defined as the ratio of unionized drug distributed between the organic and
aqueous phases at equilibrium.
P o/w = (C oil / C water) equilibrium.
The partition coefficient can provide an empiric handle in screening for some
biologic properties. For drug delivery, the lipophilic / hydrophilic balance has
been shown to be a contributing factor for the rate and extent of drug absorption.
Although partition coefficient data alone does not provide understanding of in
vivo absorption, it does provide a means of characterizing the lipophilic/
hydrophilic nature of the drug. Since biological membranes are lipoid in nature.
The rate of drug transfer for passively absorbed drugs is directly related to the
Lipophillicity of the molecule.
The partition coefficient is commonly determined using an oil phase of octanol or
chloroform and water.
Drugs having values if P much greater than 1 are classified as lipophilic, whereas
those with partition coefficient much less than 1 are indicative of a hydrophilic
Stir in beaker
of drug in
A major improvement in solubility can be achieved by forming a salt . A salt is a
chemical combination of two ionizable components one acidic and one basic
relative to the other .
Either the acidic or basic moiety may be the drug .
If pKa (acid) and pKa (base) are too close a stable salt may not form .
Some molecules do not form salts , such as those do not dissociate when dissolved
examples are steroids and alcohols .
Among cations, the most frequently found ion is sodium (62%), followed by
potassium and calcium (10%);
zinc and magnesium (3%),lithium, magnesium , di ethanolamine,
benzathine, ethyldiamine, aluminum, Chloro procaine,
and choline (in decreasing order of frequency).
the most frequently used counter ion is hydrochloride (almost 50%), followed by
sulfate(8%), bromide and chloride (5%),
Di phosphate, citrate, maleate (3%), Iodine mesylate, hydro bromide (2%), acetate,
isothionate, methylsulfate,salicylate, lactate, methyl bromide, nitrate, bitartrate,
benzoate, dihydrochloride,gluconate, carbonate, edisylate, mandelate, methylnitrate,
calcium edentate, camsylate, edentate, fumarate, glutamate,hydro bromine, napsylate,
pantothenate, stearate, gluceptate, bicarbonate, estolate,esylate, glycollylarsinate,
hexylresorcinate, lactobionate, maleate, mucate, polygalactoronate,teoclate,
and triethiodide (in decreasing order of frequency).
Fumarate 3.0, 4.4
Hydro bromide 8.0
Malate 3.5, 5.1
Phosphate 2.15, 7.20, 12.38
Succinate 4.2, 5.6
Tartrate 3.0, 4.3
The pKa values of weak acids that are most frequently used in salt formation.
A process flow for the selection of the best salt form
NSAID’s aclofenac, diclofenac, fenbrufen,
Weak acid pKa ~ 4, low solubility
Salt forms sodium
diclofenac (free acid) : 0.8 mg/ml (37 o
diclofenac sodium :24.5 mg/ml (37 o
Quinolones enoxacin, norfloxacin,
Salt forms lactate, acetate, gluconate,
Free base : < 0.1 mg/ml (25 o
Salt forms : > 100 mg/ml (25 o
Co solvents are used to solubilize the drug substance when its aqueous solubility
alone is insufficient to achieve the desired level .
The most widely used co solvent system is water/ethanol blend .
Other suitable solvents are used with water include Sorbitol ,
propylene glycol and syrup .
Example a blend of propylene glycol and water is used to improve the solubility of
co-trimoxazole in oral solutions .
SOME PRODUCTS CONTAING CO SOLVENTS
NAME CO SOLVENT COMPOSITION
Dimenhydrinate 50% propylene glycol
Hydralazine HCL 10% propylene glycol
Multivitamin infusion 30% propylene glycol
Pentobarbital sodium 40% propylene glycol , 10% ethanol
Digoxin 40% propylene glycol , 10% ethanol
Dihydroergotamine mesylate 6.1%ethanol , 15% glycerin
Reserpine 10% dimethyl acetamide , 50% polyethylene
Complexation can be analyzed and explained on the basis of “law of mass
action” as follows:
D (solid) D (solution)
xD + yC DxCy
St = [D] + x[DxCy]
D = drug molecule
C = complexing agent (ligand)
St = total solubility of free drug [D] and the
drug in the complex [DxCy]
A complex is an entity formed when two molecules , such as a drug and a
solubilizing agent (ligand) are held together by weak forces .
For complex formation to occur , drug and ligand molecules should be able to
donate or accept a pair of electrons .
LIGANDS OR COMPLEXING AGENTS….
Complex formation between the drug benzocaine and ligand caffeine can be
attributed to the dipole dipole interaction between a partial negative charge on
carboxy oxygen of benzocaine and a partial positive charge on nitrogen of caffeine
- Benzoic acid
- PEG series
The term prodrug was first used by Albert and was defined as a compound that
undergoes biotransformation prior to eliciting a pharmacological response .
The Antiviral agent ara-A has a low aqueous solubility . The formate ester of ara-A
was reported to be 66times more soluble in water than was ara-A.
Some examples of water soluble prodrugs
PARENT DRUG PRODRUG
Oxazepam oxazepam sodium succinate
Prednisolone prednisolone sodium succinate
Prednisolone prednisolone disodium phosphate
Parent corticosteroids hydrocortisone
Tetrahydrocannabinol tetrahydrocannabinol di sodium phosphate 32
A compound may be amorphous or crystalline, where the compound has more than
one crystalline form it is said to be exhibit polymorphism.
Polymorphisms generally have
Different melting points ,X-Ray diffraction patterns and solubility even though they are
Although a drug substance may exist in two or more polymorphic forms, only one form
is thermodynamically stable at a given temperature and pressure.
In general the stable polymorph exhibits the highest melting point, the lowest
solubitlity, and the maximum chemical stability.
Various techniques are available for investigation of the solid state includes
microscopy (hot stage microscopy) infrared spectrophotometry thermal analysis and X-
Ray power diffraction.
Chemical stability and solubility changes due to polymorphism can have an impact on
drugs bioavailability and its development program.
Polymorphism can be classified into 2 types.
Enantiotropic: One polymorph can be reversibly changed into another by varying
temperature and pressure.
Monotropic: One polymorphic form is unstable at all temperatures and pressures.
Ex: glyceryl stearates.
During preformulation it is important to
1.Identify the polymorph that is stable at room temperature
2.Determine whether polymorphic transitions are possible within the temperature
range used for stability studies and during processing.
A more difficult task in the study of polymorphism is determination of relative
stability of metastable polymorph and prediction of its rate of conversion with in
Some examples of drugs exhibiting polymorphism
1. Chloramphenicol palmitate
Three crystalline forms (A, B, C) and amorphous
Polymorphism A-inactive, polymorphism B-The more soluble form
Pseudo polymorphs should be identified since most polymorphs can be obtained
by changing the recrystallizing solvent. Solvents including polymorphic change are:
water, methanal, ethnol, acetone,n-butonol,n-pentonal,benzene and toluene.
Preformulation studies have a significant part to play in anticipating
formulation problems and identifying logical path in both liquid and solid
dosage form technology.
The most appropriate salt development and Stability studies in solution will
indicate the feasibility of parental or other liquid dosage form and can identify
methods of stabilization.
By comparing the physicochemical properties of each drug candidate with in a
therapeutic group, the preformulation scientist can assist the synthetic chemist
to identify the optimum molecule, provide the biologist with suitable vehicles
to elicit pharmacological response and advise the bulk chemist about the
selection and production of the best salt with appropriate particle size and
morphology for subsequent processing.
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6.M. Gibson, Pharmaceutical Preformulation and Formulation, HIS Health
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