05/03/2021

Pharmaceutical
preformulation

Preformulation
 Formulation is the process of developing a drug candidate
into a drug product.

Preformulation is an investigation of physical and chemical

properties of a drug substance alone and when combined with
excipients.

 Preformulation as the name suggests is a stage that must be

undertaken before the formulation-proper can begin.

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Preformulation
 The objective of the Preformulation studies are:
1. To establish the physical chemical properties of the new
drug entity
2. To determine the drug kinetics and stability.
3. To establish the drug compatibility with common
excipients

 Information gained in this stage will be useful in the

development of a dosage form that is bioavailable, stable
and can be mass produced.

1. Organoleptic properties
2. Solubility, dissolution rate and partitioning.
3. Bulk properties:
 Particle size
 Crystallinity and polymorphism (solid state
properties)
 Hygroscopicity
 Density
 Flow and compression properties
4. Stability and compatibility studies.

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 A preformulation program should generally begin with the

description of the drug substance.

 Color, odor and taste of the new drug must be recorded.

 Organoleptic characterization affects the different

formulation decisions that have to be made in later
stages. Examples in next slide.

 A preformulation program should generally begin with the

description of the drug substance.

 Color, odor and taste of the new drug must be recorded.

 Organoleptic characterization affects the different

formulation decisions that have to be made in later
stages. Examples in next slide.

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 Examples:
– If taste is considered to be unpalatable, a less soluble
form of the drug (salt or prodrug) could be
considered.
– Unacceptable odor or taste may force the formulator
to use flavoring agents or coat the final product.
– Unsightly or variable color may force the formulator to
use coloring agents or coat the final product.
– If the material is irritating to the skin or causing
sneezing, appropriate procedures for material
handling and personnel protection can be
developed.

Solubility
Saturation solubility: is the maximum concentration of a solution
which may be prepared at a given temperature.
Knowledge of solubility is important for the manufacturing of
injectable solutions or other solution dosage forms.
Knowledge of solubility is also important for the therapeutic
outcome: no drug will reach its ultimate therapeutic target
without first being in solution.
It has been estimated that historically, up to 40% drug
candidates have been abandoned because of poor aqueous
solubility.

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Biopharmaceutics Classification System

9 (BCS)

A scientific framework has been established for

classifying drug substances based on their:
– Aqueous solubility
– Intestinal permeability
Class I High Solubility High Permeability Examples:
Metoprolol
Class II Low Solubility High Permeability Ketokinazole

Class III High Solubility Low Permeability Cimetidine

Class IV Low Solubility Low Permeability Hydrochlorothiazide

Within this framework, the BCS can be used as a drug development

tool to justify requests for the bioavailability enhancement .

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Importance of solubility for oral dosage forms

 The bioavailability of an orally-administered drug depends primarily on its
solubility in the GI tract and its permeability across cell membranes (i.e.
absorption).
 In order to be absorbed a drug must be present in the GI fluids in a
dissolved form.

Solubility
How to determine solubility?
Solubility test:
1. Excess of API in 100 mL of solvent at constant temperature (e.g.
37 °C) is agitated for a sufficient length of time (in a closed
appropriate container).
2. Samples are withdrawn as a function of time and clarified by
filtration or centrifugation and assayed using a detection
techniques (e.g. HPLC or UV).
3. A plateau concentration, corresponding to the saturation
solubility, is found.

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Solubility
How to determine solubility?
 Preformulation solubility studies focus on the drug-solvent
systems that could be encountered during the development
and use of a drug product: solubility values that are of special
importance in early development include those in distilled
water, 0.9% NaCl, 0.1 M HCl and 0.1 M NaOH, all at room
temperature as well as SGF and SIF at 37oC.
 Solubility studies should have all factors defined including pH,
temperature, ionic strength and buffer concentrations.
Therefore, preformulation solubility studies usually involve also
pH-solubility profile, pKa determination and temperature
dependence.

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Solubility
 Early determination of solubility gives a good indicator about
the ease of formulation of a drug candidate:
 For a final product, assuming oral delivery in a solid form, solubility of
the drug above 10 mg mL-1 is preferable, to prevent bioavailability
problems.
 If needed, different mechanisms to enhance solubility may be
investigated, including:
• Micellar solubilization/ addition of surfactants
• Cyclodextrin complexation
• Use of co-solvent systems
• pH adjustment (acidic/basic drugs)

Acidic Drug

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Dissolution
 Dissolution rate: the rate at which the material dissolves.
 Dissolution is partially determined by solubility: drugs with low
solubility tend to have low dissolution rate and vice versa.
 Similarly to solubility, dissolution rate can effect in vivo
bioavailability of drugs:
 For orally delivered drugs, dissolution rate determines (to
some extent) how quickly the drug will appear in blood
stream.

Dissolution
Concentration = saturation solubility

Solution
Solid drug

Diffusion
layer

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Dissolution

Dissolution
How to determine dissolution rate of a drug?
 Compressing the drug (API) into a compact disk and testing its dissolution
in an appropriate dissolution apparatus.
 Such dissolution apparatus is different from those used for testing final
dosage forms (i.e. tablets or capsules – studied later on in the course).

http://www.just.edu.jo/~sfg/Preformulation_files/slide0038_image030.jpg

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Partitioning
 No solute has complete affinity for either a hydrophilic or
lipophilic phase.

 In the context of preformulation, it is important to know early in

the drug development stage how a molecule will distribute
between aqueous and fatty environments.

 Partition coefficient is an indication of lipophilicity which

affects permeability.

Partitioning
The octanol/water partition coefficient

P
Log P < 1 Low Permeability.
Log P 1-2 Relatively permeable.
Log P > 2 Highly permeable.

 This can give an indication of the drug’s ability to diffuse

across cell membranes in vivo.

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Partitioning
 The most common method for determining partition and
distribution coefficients is the shake flask method.
 In this technique:
 The drug is shaken between octanol and water layers.
 Then aliquots from the two phases are taken and
analyzed for the drug content.
 The values of the partition coefficient obtained from this
type of experiments is affected by temperature, pH and
buffer ions.

Bulk properties

1. Particle size.
2. Crystallinity and polymorphism (solid state
properties).
3. Hygroscopicity.
4. Density.
5. Flow and compression properties.

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Particle size
 Importance:
 Physical stability of suspensions and emulsions.
 Flow properties (e.g. for solid dosage forms).
 Dissolution rate.
 Main methods of analysis:
 Sieve method
 Microscopy
 Laser diffractometers.

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Phenobarbitone

Solid state properties

 Solid particles are made up of molecules, atoms or ions that

are held in close proximity to each other.
 Solid may be crystalline or amorphous.
 The crystallinity of a drug substance can affect many aspects
of formulation, processing, as well as in vivo behavior.
 Hence, it must be well characterized during the
preformulation stage.

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Solid state properties

Crystalline state
 Crystalline materials are those in which the units (i.e. molecules, ions
or atoms) are packed in a defined order, and this order repeats over
and over again throughout the particle of solid.
 The molecules of a crystalline solid are arranged in repetitious three-
dimensional lattice units.
 These three dimensional lattice units may assume different shapes:
 Cubic as in sodium chloride
 Tetragonal as in urea
 Hexagonal as in iodoform
 Rhombic as in iodine
 Monoclinic as in sucrose
 Triclinic as in boric acid

Solid state properties

Crystalline state
Shapes of different lattice units

 Crystalline solids show definite melting points, passing rather

sharply from the solid to the liquid state.

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Solid state properties

Polymorphism
 Some materials may exist in more than one crystalline form.
Polymorphism is the property of having more than one
crystalline form.
 These different crystalline forms of the same material are called
polymorphs.
 Number of possible polymorphs ≥2
Example of polymorphism is carbon
than can exist both as diamond and
graphite.

Solid state properties

Polymorphism - example
1. The molecules in (a) are more distant than those in (b).
 it is likely that (a) is a less dense solid than (b)
2. It looks that it would be easier to physically pull a
molecule off structure in (a) than in (b), as the
molecules in (b) are more interlinked into the structure.
It is likely that:
 (a) has a lower melting point than (b); (a) might
dissolve more easily than (b)
3. If pressure was applied it appears that (a) would
break easily, as there are natural break lines, whereas
(b) does not seem to have obvious break lines.
 milling and compaction properties of the two forms
differ.

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Solid state properties

Polymorphism
 Key concept: different polymorphs have different physical
properties (e.g. melting points, density, hardness, and
solubilities).

 These properties are very important in pharmaceutical

processes, including dissolution and formulation.

 Generally there is a correlation between solubility and

melting point
 high melting point = strong lattice = hard to remove molecules = low
dissolution rate

Solid state properties

Polymorphism

Comparison of mean blood serum levels obtained with chloramphenicol

palmitate suspensions containing varying ratios of alpha and beta polymorphs, following
single oral. Percentage polymorph beta in the suspension. (Aulton’s Pharmaceutics, 4th
edition)

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Solid state properties

Polymorphism – stability
 Given a compound that exhibits polymorphism, only one of the
forms will be the most thermodynamically stable.
 All the other less stable forms are called metastable.
 Transformation of the metastable forms in the most stable form
can occur (for example over long storage).

Solid state properties

Polymorphism - preformulation
 Selection of the most suitable polymorphic form of a given compound is
done in the Preformulation stage.
 Ideally, the best polymorphic form should have the following
characteristics:
 be the stable form (rather than metastable forms).
 be easy to be processed into a dosage form
 give good bioavailability
 The polymorphic form that is thought to give the best compromise
between these characteristics will be chosen to be formulated into a
dosage form.

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Solid state properties

Polymorphism - preformulation
 During preformulation, different polymorphs of the same drug
are produced and then characterized.
 Characterization of these polymorphic forms involves:
1. identification of the different polymorphs;
2. quantitative analysis of the physicochemical properties of the
different polymorphs (examples: solubility, dissolution rate,
flowability, compressibility etc.).
 According to these data, the most suitable polymorphic form is
selected.

Solid state properties

Polymorphism - preformulation
Identification of polymorphs can be carried out either by:
1. X-ray powder diffraction (XRPD)
 It is a technique in in which the pattern produced by the diffraction of X
rays through the closely spaced lattice of atoms in a crystal is recorded
and then analyzed. Each form shows a characteristic diffraction pattern.

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Solid state properties

Polymorphism – preformulation
2. Differential Scanning calorimetry (DSC)
 It allows to differentiate polymorphs on the bases of their
melting point and heat of fusion (i.e. heat required to change a
substance from the solid to the liquid state).
 DSC also allows to identify which form is stable and which is
metastable.

Solid state properties

Solvates

Solvents might get trapped in the crystalline lattice, creating

solvate.

Solvates may be also referred to as pseudopolymorphs.

In general it is undesirable to use solvates for pharmaceuticals

because the presence of retained organic solvents would be
considered as unnecessary impurity in the product.

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Solid state properties

Solid state properties

Solvates - hydrates
Solvates, where the incorporated solvent is water, are called
hydrates.
Anhydrous compounds are those that doesn’t include water in
their structure.
In hydrates, the entrapment is often in an exact molar ratio with
the crystallizing material, for example a monohydrate will have
one molecule of water for each molecule of the material. It is
possible to have different levels of hydrates; some drugs can exist
as mono, di and trihydrate (1, 2 and 3 molecules of water to each
molecule of drug).

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Solid state properties

Solvates - properties
 Hydrates have very different properties from the anhydrous
form, in the same way as different polymorphs have different
properties from each other.
 The most usual situation is for the anhydrous to have a faster
dissolution rate than the hydrate.
 As the solvated and nonsolvated exhibit differences in
dissolution rates, they may exhibit differences in bioavailability,
particularly in the case of poorly soluble drugs.

Solid state properties

Solvates - Example
 Ampicillin solubility in water:
 Anhydrate form sparingly soluble
>Trihydrate form slightly soluble
 Higher solubility of the anhydrate
form in the GI fluids compared to
the trihydrate form.
 Higher concentration of
dissolved drug available for
absorption
 Higher bioavailailability

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Solid state properties

Amorphous state
 Amorphous solids have atoms or molecules randomly
placed as in a liquid.
 Amorphous solid have different properties from the
crystalline form of the same material.

Solid state properties

Amorphous state - Tg
 Amorphous solids do not have a melting point.
 Amorphous forms have a characteristic temperature (called
glass transition temperature or Tg) at which there is a major
change in properties.
 If the sample is stored below the Tg the amorphous form will
be brittle and described as the glassy state.
 If the sample is stored above the Tg it becomes rubbery.

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Solid state properties

Amorphous state - properties
 The solubility of amorphous solids is higher than that of
crystalline solids (Advantage). Thus, whether a drug is
amorphous or crystalline affects its therapeutic activity.

 Amorphous form are often not thermodynamically stable.

Therefore: upon storage, amorphous solids tend to revert to
the most stable crystalline form (problem).

Solid state properties

Amorphous state - properties

Amorphous forms tend to absorb more easily water than

crystalline forms.

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Solid state properties

Preparation of amorphous solids
Large molecular weight species (e,g. polymers) often cannot
form crystals, therefore they tend to be present as amorphous
forms.

For low molecular weight materials, the amorphous form may

be produced if during the preparation, the solidification process
is fast. In this case the molecules might not have time to align
into crystals.

Alternatively, an amorphous form may formed by grinding (i.e.

milling) of solid crystals.

Solid state properties

Amorphous solid- Preformulation
Amorphous solid can be used to improve the bioavailability of
poorly soluble drugs.
However, often, their instability (intended as tendency to
convert into crystal forms over time) limits their application.
In the Preformulation stage, identification of an amorphous
can be achieved with XRPD and DSC.

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Solid state properties

Solids

Habit (external
Internal structure
structure)

Amorphous Crystalline

Solid state properties

Crystal habit
 As said before, the internal structure (or lattice) is the molecular
arrangement within crystalline solids.
 The crystal habit is the description of the outer appearance of
a crystalline solid, in other word the crystal habit is the external
shape of the crystal.
 There are six basic crystals shape:

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Solid state properties

Crystal habit
 A single internal structure (i.e. lattice) for a compound can
have several different habits.
 Changes in the internal structure usually gives different habits.

Solid state properties

Different external shape

(crystal habits) does not
necessary indicate
different internal
structure (polymorphs)

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Solid state properties

Crystal habit
 Cristal habit can influence properties of the drug, such as
powder flow, compressibility, specific surface area, dissolution
rate, etc.
 During preformulation, crystal habits are usually described by
their shapes under a microscope (platy, equant or massive,
needle or acicular etc.)

Hygroscopicity

 Many drug substances, especially water soluble salts forms,

have the tendency to absorb atmospheric moisture.

 Deliquescent material absorb sufficient water to dissolve

completely (MgCl2).

 Also, many drugs and pharmaceutical excipients absorb

moisture to form hydrates.

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Hygroscopicity
Changes in the moisture level of a hygroscopic material greatly
affects its physiochemical properties (including its chemical
stability).

The extent of this absorption phenomena is highly dependent

on the atmospheric humidity.

Other factors affecting the extent of absorption are :

 temperature,
 surface area of the solid
 extent of exposure

Hygroscopicity
In Preformulation, hygroscopicity of a compound is usually tested by:
1. Placing samples of the bulk drug in open containers with a thin powder
bed to assure maximum atmospheric exposure.
2. These samples are then exposed to a range of controlled relative
humidity environments.
3. Moisture uptake is then monitored at different time points.
4. Percentage-of-weight gain(due to moisture uptake) data are plotted
against time.
These preliminary results can give suggestions on formulation, handling,
packaging and storage requirements for the drug (e.g. hygroscopic drug
might require packaging with a dessicant).

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Density, flow and compression properties

 Manufacturing processes frequently involve the movement,
blending, manipulation and compression of powders.
 Density, flow and compression properties of the drug powder
will have an important influence on the manufacturing
process.
 It is important to investigate such properties early (i.e. in the
preformulation stage), so to guide later on the formulation
scientist in the formulation development.
Such properties of powders will be studied in depth in following
Chapters

Stability & compatibility studies

 Accelerated stability studies (stress testing): The drug substance
(API) is subjected to harsh conditions, in order to have a quick idea
about its stability and excipient compatibility. These test studies
include both solution and solid-state experiments.
 Drug/ excipient compatibility studies: A number of excipients of
each category (diluent, binder, lubricant) are combined with the
API and exposed to harsh storage conditions.
 Storage conditions:
 Elevated temperature: 40, 50 and 60 °C with dry conditions.
 Humidity: 75% RH.
 Light: 400 and 900 foot candle for 4 and 2 weeks,
respectively.

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Formulation recommendation
 Upon completion of the preformulation evaluation of a new
drug candidate, a comprehensive report is generally prepared
highlighting pharmaceutical characteristics and problems
associated with this molecule.
 This report should include recommendations for developing
possible formulations of the drug.

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