INDUSTRIAL PHARMACY I

UNIT 1
Preformulation Studies
Detailed Syllabus:
• Preformulation Studies: Introduction to preformulation, goals and objectives, study of
physicochemical characteristics of drug substances.
a. Physical properties: Physical form (crystal & amorphous), particle size, shape, flow
properties, solubility profile (pKa, pH, partition coefficient), polymorphism.
b. Chemical Properties: Hydrolysis, oxidation, reduction, racemisation, polymerization.
c. Pharmacokinetic Properties: BCS classification of drugs & its significance, Techniques
available to develop formulation of different BCS class drugs.
• Application of preformulation considerations in the development of solid, liquid oral and
parenteral dosage forms and its impact on stability of dosage forms. (will be covered with
respective dosage form chapters)
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 The Drug Development Cycle ~ An Overview
The process of developing a new drug can take between 10 and 15 years with an estimated cost of $800 million

Discovery/Pre-Clinical Testing

• Time: 6.5 Years

Phase I

• Time: 1.5 Years

Phase II: Safety and Efficacy

• Time: 2 Years

Phase III

• Time: 3.5 Years

Marketing Approval Process

• Time: 1.5 Years

Is any consideration needed before Is any consideration needed before
formulating a solid dosage form? formulating a liquid dosage form?

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• Defined as
Preformulation
Assess physicochemical properties of drugs and excipients
Affect drug performance
Development of efficacious dosage form

• Which
Safe &
• Why efficacious
Physical / chemical properties need to be assessed?
dosage form
• How development

• What Result is Result is NOT

acceptable? acceptable?
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Goals and objectives of preformulation studies:

• To anticipate
formulation problems
& identify rationale for
development of
solid/liquid DF.

• To identify adequate
drug solubility for
selecting best salt OR
identifying need for
molecular
modification.

• To confirm absence of
significant barriers for
dosage form
development.
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8
Project team – Representative from different disciplines

Different Disciplines
• Medicinal Chemistry and Pharmacology

• Pre-formulation Research

• Formulation development

• Process R&D

• Analytical R&D

• Toxicology and drug metabolism

 I Compound Identity
Analytical Methods
II Structure VII • HPLC Assay
• TLC Assay
III Formula & Mo. Wt. • UV/Vis Spectroscopy
• Synthetic Route
Therapeutic Indication • Probable Decay Products
IV • Probable Human Dose
• Desired Dosage Form(s)
• Bioavailability Model(s)
• Comparative Products Key Dates
VIII • Bulk Scale up
• Toxicology Start Date
V Potential Hazards • Clinical Supplies Prep.
• IND Filing
Initial Bulk Lots • Phase I Testing
VI • Lot Number
• Crystallization Solvent(s)
• Particle Size Range IX Critical development Issue(s)
• Melting Point
• % Volatiles
• Observations

Essential information helpful in designing preformulation evaluation of a new drug

 Why Preformulation studies are required?
Preformulation studies are an important foundation tool early in the development of both API and drug
products.

They influence….

 Selection of the drug candidate itself

 Selection of formulation components

 API & drug product manufacturing processes

 Determination of the most appropriate container closure system

 Development of analytical methods

 Assignment of API retest periods

 The synthetic route of the API

 Toxicological strategy
Principle areas of Preformulation
Bulk properties Physico-chemical properties
• Organoleptic properties • Solubility analysis (pKa, pH)
• Crystallinity, Amorphous nature • Ionization
• Polymorphism • Partition coefficient
• Water adsorption • Dissolution
• Particle size, shape, and surface
area
• Bulk density
• Adhesion
• Powder flow
• Compressibility
Biopharmaceutical properties
Stability • Absorption (route, rate, extent, mechanism, absorption windows, food
effects)
• Solid state (RH, oxygen, light, compatibility)
• Metabolism (first pass metabolism, enzyme induction, metabolism in GIT)
• Solution state (pH, buffers, solvent, temperature)
• Duration of action (dosing, controlled release)
• Compatibility with excipients
• Dose
Organoleptic properties:
1. Appearance: Formulation should be elegant in appearance. E.g. Coloured drug distributed in white
excipient bulk gives mottled appearance to the tablet. This can be corrected by changing the
excipients or by tablet coating.

2. Taste: Taste of drugs administered orally should be monitored at preformulation stage. E.g.
Approaches used to conceal the undesirable taste include:

a. Film coating of tablets

b. Formulation in syrup dosage form, capsule dosage form

3. Touch: Dosage forms should not contain gritty particles or irregular surfaces. E.g. The tablets
should have smooth surfaces and not the irregular ones resulting from sticking to die cavity.

4. Odour: Obnoxious odour of drugs should be concealed. e.g. Cod liver oil is formulated as soft-gel
capsule which conceals its strong odour.
 Physical properties of drugs:
• Physical form:

1. Drugs can be used therapeutically as solids, liquids or gases.

2. Due to the dose uniformity and stability concerns, liquid drugs are used less frequently
than solids, whereas gases are used rarely.

3. Formulation difficulties of solid preparations are low as compared to that of liquid

preparations. Hence, practically, development of solid dosage forms get the preference.

e.g. Solid drug - Paracetamol (analgesic, antipyretic)

Liquid drug - Amyl nitrite (vasodilator)

Gaseous drug - Nitrous oxide (general anaesthetic)

LIQUIDS -

Liquids are generally volatile hence, evaporation loss should be prevented by appropriate
sealing.

E.g. Amyl nitrite is clear yellowish liquid which is volatile at low temperatures also. It is kept
in small sealed glass ampules wrapped with gauze. During administration, glass is broken
between fingertips, liquid wets the gauze and vaporizes, which is inhaled by the patient
requiring vasodilation activity.

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E.g. Propylhexedrine is a nasal inhalant used for its vasoconstrictor action. A cylindrical roll
of fibrous material is impregnated with the drug and the saturated cylinder is placed in
suitable container paired with tight cap.

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 E.g. To formulate into a tablet dosage form, liquids require chemical modification. Exception
is nitroglycerine, which is formulated as sublingual tablets for treatment of angina.

• Usually, for oral administration of liquid drug in solid dosage form, it is either formulated as
a soft gelatin capsule (e.g. vit. A, E, D) or developed into a suitable solid salt.

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E.g. Scopolamine is a viscous liquid which is developed into a salt form that will be suitable
for tablet or capsule formulation (e.g. Scopolamine hydrobromide).

When applied topically, liquid nature holds advantage in therapy. E.g. Undecylenic acid
enhances topical treatment of fungal infections of skin.

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Conclusion:
1. Liquid API can be easily formulated into inhalation, transdermal and topical dosage
forms.
2. For oral administration of liquid API in solid dosage form, it is either formulated as a
soft-gelatin capsule or developed into a suitable solid salt.

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SOLIDS -

• Crystal habit (outer appearance) and crystal lattice (internal structure) of solid drugs can
affect its bulk and physicochemical properties.

• Crystal habit is description of outer appearance of crystals (e.g. prismatic, acicular, platy etc.)
and internal structure (crystal lattice e.g. monoclinic, triclinic, rhombic, orthorhombic etc.) is
the molecular arrangement within the solid.

• A single internal structure can have several different habits.

Crystal habit Crystal lattice 21

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Crystalline or Amorphous:

• Depending upon internal structure, compounds can be classified into crystalline and amorphous.

• Crystalline form contain crystal lattice i.e. repetitious spacing of constituent atoms or molecules
in a 3D array.

• Amorphous forms have randomly placed atoms and molecules i.e. no crystal lattice.

• Characterization of solids involves:

i. Verifying that solid is the expected chemical compound (since crystal lattice depends upon
bond lengths and bond angles formed between different atoms present in the molecule)

ii. Characterizing the internal structure (crystal lattice type the compound)

iii. Describing the habit of crystal (morphology of crystals)

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• During characterization of physical form, determining whether the solid is amorphous or crystalline
is important.

• Since amorphous forms usually have higher thermodynamic energy than corresponding crystalline
forms, solubilities and dissolution rates of amorphous forms are generally higher.

• But, upon storage, amorphous solids tend to revert to more stable form, resulting into instability
during bulk processing or within dosage forms.

• Amorphous forms are typically prepared by rapid precipitation, lyophilization or rapid cooling of
liquid melts. 24
• Identification of hydrates is necessary since aqueous solubilities of hydrates are usually
lower than their anhydrous forms.

• Conversion of anhydrous compound to hydrate within the dosage form may reduce the
dissolution rate and subsequent bioavailability.

E.g. Anhydrous ampicillin is more soluble than its trihydrate form.

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Polymorphism

• Polymorphism is the ability of compound to exist in form of more than one crystal
structure or crystal lattice.

• Chemical stability, solubility and dissolution rate varies with polymorphism and
impacts formulation development and bioavailability of drug.

E.g. Chloramphenicol palmitate exists in three polymorphic forms A, B and C.

Absorption of Chloramphenicol from oral suspension containing A and B forms

increases as a function of increase in % of B (i.e. the more soluble polymorph).

The A form is unstable at room temperature and gradually transforms to B on storage.

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• Methods used for characterization of solid forms include:

1. Microscopy – Polarized Light Microscopy, Scanning Electron Microscopy (SEM),

Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM), Hot Stage
Microscopy (HSM)

2. Thermal analysis - Differential Scanning Calorimetry (DSC), Differential Thermal Analysis

(DTA), Thermogravimetric Analysis (TGA)

3. X-ray powder diffraction (XRD)

4. Infrared (IR) spectroscopy

5. Solubility analysis/ Dissolution

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1. Microscopy:

• Isotropic substances have single refractive indices. E.g. Amorphous solids or substances
with cubic crystal lattice like NaCl. They do not transmit light and hence appear black
against black polarized background.

• Anisotropic substances have more than one refractive indices and appear bright against
black polarized background. They can be uniaxial (2 RI) or biaxial (3 RI).

• Most drugs are biaxial with either an orthorhombic, monoclinic or triclinic crystal systems.

• Using polarizing microscope, crystal morphology (crystal habit) of different polymorphs

can be identified. Polarizing microscope fitted with a hot stage can be used for identifying
polymorphism in drugs.

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LHS RHS LHS RHS

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AFM images

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 2. Thermal analysis:

• 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.

• Endothermic processes: Fusion, melting, boiling, sublimation, vaporization, desolvation, chemical degradation.

• Exothermic processes: Crystallization and degradation.

• Quantitative measurement of these processes (number of exothermic or endothermic peaks in the graph) give

information about purity, polymorphism, solvation, degradation and excipient compatibility at

preformulation stage.

(Upward or downward
direction of peak depends
upon y-axis label)
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• Thermogravimetric analysis (TGA) measures changes in sample weight as function of time or

temperature. It is used to monitor desolvation or decomposition processes.

E.g. Door polymer (in image)

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Presence of 10% dihydrate form of an acetate salt of an organic amine can be detected by DSC as
well as TGA.

• For an acetate salt of an organic

amine, anhydrous form shows
DSC
only single endotherm at 155 °C.
But dihydrate form shows an
endotherm between 70-90 °C, due
to loss of two water molecules.

• % weight remaining for dihydrate

form is lesser after 70-90 °C due to
TGA loss of water molecules.
• % weight remaining for anhydrous
form is same throughout the
studied temperature range.

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3. X-ray powder diffraction (XRD):

• Batch-to-batch reproducibility of crystalline form can be

determined using this technique.

• Diffraction pattern is characteristic of specific crystalline

lattice of a given compound. Amorphous forms does not

produce diffraction pattern.

• Single crystal x-ray analysis provides identification and

description of crystal lattice of crystalline material.

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Particle size and shape:
• Effect of particle size and shape on API: It affects

i. Bulk flow from hopper during manufacturing (spherical shape is preferred due to reduced
interparticle friction)

ii. Formulation homogeneity (uniformity of dose). It is maintained when particle size is uniform.

iii. Surface area - Dissolution and degradation increases with decreased particle size.

• Effect of particle size and shape on formulation:

i. Variation in granule/ particle size and size distribution can introduce weight variation in final DF
such as tablet/ capsules. This in turn affects uniformity of dose.

ii. Affects stability of suspensions: Sedimentation rate and elegancy is better for flocculated
suspensions. 35
• Effect of particle size and shape on stability of formulation/ API :

i. Stability of formulation/ API decreases with increase in surface area (due to

increase in surface exposed for degradation).

ii. Stability of suspension sometimes decreases with decrease in particle size as

the sediment formed on long storage may lead to caking.

• Effect of particle size and shape on bioavailability of API from formulation:

i. Smaller particle size  larger surface area. Hence, increased rate of

dissolution resulting into increased absorption and bioavailability.
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Particle size and shape:

Methods of particle and size and shape determination:

a. Light microscopy (self-study, revise)

b. Sieve method (self-study, revise)

c. Sedimentation method (self-study, revise)

d. Coulter counter method

Coulter method of sizing and counting particles is based on measurable changes in electrical
impedance produced by non-conductive particles suspended in an electrolyte. A small
orifice (aperture) between electrodes is the sensing zone through which suspended
particles pass. 37
Powder flow properties:
1. Free-flowing powders and non-free flowing powders

2. Flow property is affected by changes in particle size, density, shape & moisture content.

3. Granulation step forms sphere-like or regularly-shaped aggregates called granules. It

improves flow properties by reducing inter-particle friction in powder bulk.

4. Characterization of free-flowing powders:

i. Flow rate apparatus

ii. Percent compressibility / Carr’s consolidation index (self-study, revise)

iii. Angle of repose (self-study, revise)

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• Flow rate apparatus:

1. This apparatus consists of a grounded metal tube from which

drug flows through an orifice onto an electronic balance, which
is connected to a strip chart recorder.

2. Several flow rate (g/sec) determinations at each of a variety of

orifice sizes (1/8 to ½ inches) should be made.

3. In general, greater the standard deviation between multiple

flow rate measurements, the greater is the weight variation in
products produced from that powder.

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• Percent Compressibility or Carr’s index:

1. Bulk density varies with method of crystallization, milling or formulation.

2. Density problems can be corrected by milling, slugging or formulation.

3. Bulk density is very important for

i. Selecting size of high-dose capsule product. Slugging reduces bulk volume and facilitates
capsule filling.

ii. Homogeneity of low-dose formulation (sedimentation rate).

4. Methods of evaluation:

Bulk density, Tapped density, True density (self-study, revise)

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41
Solubility Profile:
1. Solubility of drugs and excipients depend upon following factors:

a. pKa of solute

b. pH solubility profile

c. Partition coefficient

d. Temperature of solution

e. Solubilization mechanism

f. Rate of dissolution

g. Dielectric constant of solvent

Hence, these parameters are determined during Preformulation solubility studies.

These properties depend upon solute as well as solvents.

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1. Drug’s solubility profile & possible solubilization mechanisms can provide information on absorption

& bioavailability of API from formulation.

2. Preformulation solubility studies focus on drug-solvent systems that could occur during the delivery of

drug candidate. E.g. Solubility of orally administered drug is checked in isotonic media with acidic pH.

3. Solubility values are generally established for solubility in distilled water, 0.9%w/v NaCl, 0.01M HCl,

0.1M HCl, 0.1M NaOH and pH 7.4 buffer, all at room temperature and at 37°C.

4. For equilibrium solubility determination, excess drug dispersed in solvent is agitated at a constant

temperature. Samples of slurry are withdrawn at various time intervals and clarified by centrifugation.

The clear supernatants are assayed to establish a plateau concentration. The solid precipitate is also

characterized to establish the equilibrium solid form of the drug.

5. Solubility measurements can be done by HPLC, UV, fluorescence spectroscopy or Gas chromatography.
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Solubility based classification of Drug

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pH and pKa:
1. Solubility of drug & hence absorption and bioavailability can be altered with pH of solution.
Thus, determination of dissociation constant of drugs capable of ionization within pH range of 1-
10 is important.

2. pKa value indicate strength of an acid/ base.

3. pKa is the negative log of acid dissociation constant (Ka). A lower pKa value indicates stronger
acid and higher pKa value indicates stronger base.

4. pKa is pH at which 50% compound is in its ionized form and 50% is in its unionized form.
5. pKa determination is done by UV-Vis spectroscopy or potentiometric titrations.

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6. For weakly acidic drug (e.g. aspirin) with pKa greater than 3, un-ionized form is present within
the acidic contents of the stomach. The drug is predominantly ionized in the neutral media of
intestine.

7. For basic drugs such as erythromycin and papaverine, the ionized form is predominant in stomach
as well as in intestine.

8. Unionized form is absorbed from GIT due to efficient permeation. However, rate of dissolution,
lipid solubility, common-ion effect and metabolism in GI tract can be altered with pH changes.

9. Hence, pH of gastric environment and pKa of drug determine its ionization, which in turn affects
its solubility-permeability and bioavailability.

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Partition coefficient:
1. Oil/water partition coefficient gives an indication of its ability to cross cell membranes.

It can be measured in octanol/water or chloroform/water systems.

2. Partition coefficient is defined as the ratio of drug distributed between organic and

aqueous phase at equilibrium.

3. It alone does not provide data on drug absorption, but it gives an idea about

hydrophilic/ hydrophobic nature of drug.

4. A negative or near zero value for log P means it is more hydrophilic; while a

positive value nearing 5 and above denotes the compound is more lipophilic.

5. Lipophilic value indicates potential of API to cross blood brain barrier and vice versa. It

can either potentiate desired CNS therapeutic activity (e.g. levodopa) or show

unwanted CNS side effects (like sedation) based on its site of action.
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Chemical properties of drugs:
Since the chemical composition of drugs vary, their chemical degradation pathways also vary. Same
drug can undergo several simultaneous decomposition reactions at a time.
E.g. Vitamin A undergoes both isomerization and oxidation.

Common chemical reactions that drugs undergo include:

• Hydrolysis

• Oxidation

• Reduction

• Racemisation

• Polymerization

Usually such chemical reactions result into degradation of APIs and excipients, which cause instability
of products/formulations.
Hydrolysis:
• Hydrolysis is the reaction of compound with water and can be classified into ionic and molecular
forms of hydrolysis.

• Ionic hydrolysis occurs when salts of weak acids (e.g. potassium acetate) or weak bases (codeine
phosphate) interact with water. It is an instantaneous equilibrium process.

• Molecular hydrolysis is much slower and irreversible process that includes cleavage of the drug
molecule. It is mainly responsible for decomposition of pharmaceutical products. E.g. esters like
local anaesthetics (amethocaine, benzocaine), amides like sulphonamides and nitriles.

• Molecular hydrolysis is usually catalysed by proton or hydroxyl ions and hence, rate of
decomposition critically depends upon the pH of the system.

• Although hydrolysis occurs principally with drugs in aqueous solutions, suspensions and solid
dosage forms are also susceptible to same.
Oxidation-reduction:
• Oxidation can be defined as removal of electropositive atom or electron, or addition of an
electronegative atom (i.e. removal of hydrogen/ electrons or addition oxygen).

• Reduction can be defined as removal of electronegative atom or addition of an

electropositive atom or electrons (i.e. removal of oxygen or addition hydrogen/ electrons).

• Oxidation processes may proceed slowly under the influence of atmospheric oxygen (auto-
oxidation) or may involve loss of electrons without addition of oxygen.

• Some substances undergoing oxidation inlude morphine, adrenaline, fixed oils, volatile oils,
etc.
• Auto-oxidation:

• It occurs under the influence of atmospheric oxygen. Oils and fats containing unsaturated
linkages are the most susceptible molecules.

• E.g. Volatile oils such as clove and cinnamon oils, fixed oils such as ethyl oleate, arachis oil.

• It usually alters the organoleptic properties of drugs such as colour, odour and taste.

• In majority of cases, auto-oxidation is a chain reaction involving formation of free-radicals.

It comprises of three steps: 1. Initiation, 2. Propagation and 3. Termination

• Final products of auto-oxidation are aldehydes, ketones and short-chain fatty acids.
• Oxidation due to loss of electrons without addition of oxygen:

• E.g. Adrenaline, riboflavin, ascorbic acid.

• When two potentially oxidizable compounds are present together, compound with the
lower E0 will be oxidized in preference to compound with higher E0 (where, E0 is standard
oxidation-reduction potential).

• Hence, stabilization of an oxidizable drug can be achieved by incorporation of a compound

with lower E0 value in the formulation. E.g. Ascorbic acid is used to protect adrenaline from
oxidation in the solution (anti-oxidants/ preservatives).
Racemization:
• It involves conversion of an optically active form of a drug into its enantiomorph. The process continues until
there are equal concentrations of both the optically active forms. At this point, drug solution no longer
rotates the plane of polarized light, denoting loss/ decrease of activity.

• When racemization is complete, drug still retains some potency, since 50% drug is in active form. Sometimes
the enantiomorph possesses certain degree of activity (desirable or undesirable too). E.g. (-)hyoscyamine is
converted into atropine i.e. (-)(+)hyoscyamine by the action of heat or alkali. As a mydriatic, atropine is less
potent and it has other anti-cholinergic effects too.

• Usually, levo-rotatory form of drugs show greater biological activity. E.g. (-)adrenaline, (-)phenylephrine, (-
)cetirizine.

• Presence of aromatic groups in structures increase the susceptibility of compound to racemization.

• Rate of racemization depends upon factors such as presence of catalytic hydrogen or hydroxyl ions, heat and
light. E.g. Racemization of (-)adrenaline is catalysed by hydrogen ions, hence low pH decomposes the drug.
Polymerization:
• It involves combination of two or more identical molecules to form a much larger and more
complex molecule. It usually occurs as degradation of primary decomposition products.

• E.g. Antiseptic formaldehyde forms polymer paraformaldehyde in cold conditions.

Methanol is added as a stabilizer to prevent polymerization.

• At acidic pH values, dextrose injection degrades on autoclaving due to depolymerization

reaction which forms 5-hydroxymethylfurfural as decomposition product.

• Primary oxidation product of adrenaline, adrenochrome, undergoes further oxidation

which gives black and brown polymeric pigment.
Chemical stability analysis:

Solution stability study

Solid state stability study

Solution stability study:
Objective: Identification of conditions necessary to form a stable solution. Conditions s.a. effects of pH, ionic
strength, co-solvent, light, temperature and oxygen.

E.g. Solution stability investigation should confirm API degradation at extreme pH and temperature conditions. i.e.
testing with 0.1N HCl, water and 0.1N NaOH at 90° C.

For oxidation testing, solutions should be subjected to

• Excessive headspace of oxygen
• Headspace of inert gas such as helium or nitrogen
• In-organic anti-oxidant like sodium metabisulphite
• Organic anti-oxidant like butylated hydroxytoluene (BHT)

Headspace composition can be controlled if samples are stored in vials for injection that are capped with Teflon-
coated rubber stoppers. Stoppers are penetrated with needles and headspace is flooded with desired atmosphere.
Resulting holes are sealed with wax to prevent degassing.
Solid state stability study:
Objective: Identification of stable storage conditions for drug in solid state and identification of compatible
excipients for formulation. Solid state reactions are much slower and difficult to interpret than solution-state
reactions, due to reduced number of molecular contacts between drug and excipient molecules.

E.g. Polymorphic changes are detected by quantitative IR or DSC.

Surface discolouration due to oxidation or reaction with excipients can be detected using surface reflectance
measurements or diffuse reflectance measurements.

Procedure of solid state stability testing:

Weighed samples are placed in open-screw cap vials and exposed to different conditions of temperatures,
humidity and light for up to 12 weeks. Almost 5-10 mg samples are analysed by HPLC and 10-50 mg samples by
DSC and IR. Samples are also analysed for oxidation by flooding headspace with oxygen/ nitrogen. Samples are
then analysed for chemical stability, polymorphic change and discolouration.
 BCS Classification
The Biopharmaceutics Classification System (BCS) is a scientific framework for classifying drug
substances based on their aqueous solubility and intestinal permeability.

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Significance of BCS classification:
In terms of formulation aspects
• BCS classifies drugs into four classes according to their dose, their aqueous solubility
across gastrointestinal (GI) pH range and their permeability across GI mucosa.

• It is useful to classify drugs and predict their bioavailability issues.

• Highly soluble: Highest dose strength is soluble in 250 ml or less of aqueous media
over the pH range 1-8.

• 250 mL limit is derived from minimum volume anticipated in the stomach when a
dosage form is taken in the fasted state with a glass of water.

• If volume required for solubilization is greater than 250 mL then drug is considered to
have low solubility. 59
• A drug is considered to be highly permeable when extent of absorption in humans is
expected to be more than 90% of the administered dose.

• Class I drugs: propranolol and metoprolol

• Since they dissolve rapidly, they can be formulated as immediate release oral dosage
forms unless they form insoluble complexes or are unstable in gastric fluid or undergo
first pass metabolism. They are rapidly absorbed and hence show good bioavailability.

• Class II drugs: ketoprofen, carbamazepine

• Low solubility: Hence dissolution rate is rate-limiting step in oral absorption.

Formulation approaches should improve the dissolution rate and hence oral
bioavailability.
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• Class III drugs: ranitidine, atenolol

• Since they dissolve rapidly but are absorbed slowly, drug should be released
rapidly from the dosage form to maximize contact time of drug with GI
epithelium, which in turn would increase its permeation.

• Class IV drug: hydrochlorothiazide and furosemide

• Shows poor oral bioavailability, hence not suitable for oral route. Prodrug
formation, NDDS (novel drug delivery systems), alternative route of
administration may help to improve their absorption into systemic circulation.
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Significance of BCS classification:
In terms of regulatory approval of generic products
• The principle of BCS is that if two drug products yield the same concentration profile along the GI
tract, they will result in same plasma profile after oral administration.

• This concept underlying BCS finally led to introducing the possibility of waiving in vivo bioequivalence
(BE) studies in favor of specific comparative in vitro testing to conclude BE of oral immediate release
products with systemic actions.

• In terms of BE, it is assumed that highly permeable, highly soluble drugs housed in rapidly dissolving
drug products will be bioequivalent and that, unless major changes are made to the formulation,
dissolution data can be used as a surrogate for pharmacokinetic data to demonstrate BE of two drug
products.

• BCS thus enables manufacturers to reduce cost of approving scale-up and post-approval changes to
certain oral drug products without compromising public safety interests. 62
 Techniques of solubility enhancement*
• Physical modifications • Chemical modifications • Miscellaneous methods
1. Particle size reduction/ 1. Change in pH 1. Co-solvency
Micronization & 2. Salt formation 2. Hydrotrophy
Nanosuspension
3. Use of buffer 3. Selective adsorption
2. Modification of crystal habit
4. Complexation 4. Use of soluble prodrug
 Polymorphs
5. Derivatization 5. Use of solubilizing agents
 Amorphous form
6. Supercritical fluid process
 Cocrystallization
7. Use of adjuvant like
3. Drug dispersion in carriers surfactants
Solid dispersions
8. Use of novel excipients
Eutectic mixtures *There are several other
Solid solutions techniques. Discussion is
restricted only to few
Cryogenic techniques techniques.
Particle size reduction or Micronization
• High energy particle size reduction technique can convert coarse particles into particles <5 μ in dia.

• Uniform & narrow particle size distribution can be obtained, which is essential for developing
uniform dosage form.

• Drugs like Griseofulvin, chloramphenicol, tetracycline salts have shown 50% more absorption rate in
their micronized form.

• Micronization process was also applied to progesterone, spironolactone diosmin, and fenofibrate.

• As micronization occurs surface area increases with decreasing particle size & increase in rate of
dissolution. But it does not increase equilibrium solubility.

• Further decrease in particle radius (smaller than micron level) may decrease solubility because any
change on particle may affect static charge present on particle, which may decrease solubility.
• Techniques for Micronization: Milling using a Jet mill, Colloid mill, fluid energy mill or micronizer;
spray drying, supercritical fluid technology; Gas anti-solvent recrystallization precipitation etc.
• Advantages:

• Micronization results in higher dissolution rates.

• It helps to decrease dose of certain drugs because of increased absorption efficiency.

• For e.g. Griseofulvin dose was reduced to half following micronization.

• Disadvantages:

• Mechanical forces inherent to comminution, s.a. milling & grinding, often impart significant
amounts of physical stress upon drug product which may induce degradation.

• Thermal stress which may occur during comminution & spray drying is a concern when processing
thermosensitive or unstable active compounds.
Inclusion Complex Formation-Based Technique
• Complexation is a reversible association b/w 2 or more molecules to form a non-bonded entity with
a well-defined stoichiometry. Complexation relies on relatively weak forces such as van der Waals
forces, hydrogen bonding and hydrophobic interactions.

• Inclusion complexes: They are formed by insertion of nonpolar region of one molecule (Guest) into
non-polar cavity of another molecule (or group of molecules) (Host).

• When guest molecule enters the host, contact b/w water and nonpolar regions of both is reduced.

• Most commonly used host molecule is CYCLODEXTRIN. CDs are nonreducing, crystalline, water
soluble, and cyclic oligosaccharides consisting of glucose monomers arranged in a donut shaped ring
having hydrophobic cavity and hydrophilic outer surface. E.g. of few drugs whose solubility and
hence bioavailability increased by cyclodextrin include itraconazole, hydrocortisone, diazepam,
digitoxin etc.
 Representation of hydrophobic
cavity and hydrophilic (a) 1:1 and (b) 1:2 drug
outer surface of cyclodextrin cyclodextrin complexes

Three naturally occurring CDs are α-Cyclodextrin, β-Cyclodextrin, and γ-Cyclodextrin

68
• Kneading Method – impregnating CDs with little amount of water or hydroalcoholic solutions to
convert into a paste. Drug is then added to the above paste and kneaded for a specified time. In
large scale, kneading can be done by utilizing the extruders and other machines.

• Lyophilization/Freeze-Drying Technique – For high degree of interaction b/w drug and CD,
lyophilization technique is considered suitable. Here, solvent from solution is eliminated through
primary freezing & subsequent drying of solution containing both drug and CD at reduced pressure.
Thermolabile subs can be successfully made into complex. Limitations include use of specialized
equipment, time consuming process, and yield poor flowing powdered product. This method is an
alternative to solvent evaporation & involved molecular mixing of drug & carrier in common solvent.

• Microwave Irradiation Method – microwave irradiation reaction between drug and complexing
agent using a microwave oven for short time of about one to two minutes at 60◦C. This method is
suitable ofr industrial scale preparation due to shorter reaction time and higher yield of product.
Limitations of Complexation

• Cyclodextrins are very expensive materials.

• In some cases when complexing agent is too concentrated, the complex can precipitate out of
solution.

• Natural cyclodextrins are not useful for parenteral drug delivery as they possess renal and
cytotoxicity. Thus, some of the chemically modified cyclodextrins are used. E.g. Hydroxypropyl and
sulfobutyl ether derivatives.

• Limiting factor for use of cyclodextrins is the ability of a drug to form a complex with the cyclodextrins
internal cavity. The entrance to the cavity of cyclodextrins may have hydroxyl groups or bulky alkyl
groups that may provide steric restrictions to the encapsulation of drugs.
Modification of crystal habit (Crystal engineering)
• Crystal engineering techniques are developed for controlled crystallization of drugs with well-defined
particle size distribution, crystal habit, crystal form (crystalline or amorphous), surface nature, and
surface energy.

• By manipulating the crystallization conditions (use of different solvents or change in the stirring or
adding other components to crystallizing drug solution), it is possible to prepare crystals with different
packing arrangement; such crystals are called polymorphs.

• As a result, polymorphs for the same drug may differ in their physicochemical properties such as
solubility, dissolution rate, melting point, and stability.

• E.g. Tablets prepared from form A polymorph of oxytetracycline dissolved significantly more slowly
(55% dissolution at 30 min) than the tablets with form B polymorph (95% dissolution at 30 min).
• Crystal engineering approach also involves the preparation of hydrates and solvates for enhancing dissolution
rate.

• During crystallization process, it is possible to trap molecules of solvent within the lattice. If solvent used is
water, the resultant crystal is a hydrate; if any other solvent is used, it is referred to as solvate.

• E.g. Glibenclamide as pentanol & toluene solvates, exhibited higher solubility and dissolution rate than two
non-solvated polymorphs.

• In general, it is undesirable to use solvates for drugs and pharmaceuticals as the presence of organic solvent
residues may be toxic.

• It is possible for the hydrates to have either a faster or slower dissolution rate than anhydrous form. Most
usual situation shows anhydrous form having faster dissolution rate than hydrate. E.g. Dissolution rate of
theophylline anhydrate was faster than its hydrate form. In certain cases, hydrate form of the drug may show
rapid dissolution rate than its anhydrous form. E.g. Erythromycin dihydrate exhibited higher dissolution rate
than monohydrate & anhydrate forms.
• Amorphous form of drug is always more suited than crystalline form due to higher energy associated
and increased surface area.

• However, amorphous region is thermodynamically unstable and therefore susceptible to

recrystallization on storage particularly in hot and humid condition.

• Pharmaceutical cocrystals are formed between a molecular or ionic drug and a cocrystal former to
create a new crystal form whose properties are often superior than the separate entities. E.g.
Carbamazepine: saccharin cocrystal showed superior stability, dissolution, suspension stability, and
oral absorption profile in dogs.
Drug dispersion in carriers
• Solid dispersions represent a useful pharmaceutical technique for increasing the dissolution, absorption, and
therapeutic efficacy of drugs in dosage forms.

• Concept of solid dispersion was originally proposed by Sekiguchi and Obi, who investigated generation &
dissolution performance of eutectic melts of a sulphonamide drug and a water-soluble carrier in early 1960s.

• The term solid dispersion refers to a group of solid products consisting of at least two different components,
generally a hydrophilic matrix and a hydrophobic drug.

• The most commonly used hydrophilic carriers for solid dispersions include polyvinylpyrrolidone (Povidone,
PVP), polyethylene glycols (PEGs), Plasdone-S630. Surfactants like Tween-80, docusate sodium, Myrj-52,
Pluronic-F68, and sodium lauryl sulphate (SLS) also find a place in the formulation of solid dispersion.

• Solubility of celecoxib and ritonavir were improved by solid dispersion using suitable hydrophilic carriers like
povidone and gelucire, respectively.
• Various techniques to prepare solid dispersion of hydrophobic drugs include

• Hot-Melt Method (Fusion Method) - Important requisite for this technique is the miscibility of drug
and carrier in the molten form and their thermostability.

• Solvent Evaporation Method - Advantage is that thermal decomposition of drug/ carrier can be
prevented due to low temp. requirement for evaporation of organic solvents. However, disadvantage
include high cost of preparation, difficulty in complete removal of organic solvent, possible adverse
effect of negligible amount of solvent on chemical stability of drug, selection of common volatile
solvent, and difficulty in reproducing crystal forms.

• Hot-Melt Extrusion - Same as fusion method except that intense mixing of components is induced
by an extruder. Possibility of continuous production, which makes it suitable for large-scale
production.
Nanosuspension
• Pharmaceutical nanosuspension is a biphasic system consisting of nano-sized drug particles
stabilized by surfactants for either oral, topical, parenteral or pulmonary use.

• Particle size distribution in nanosuspensions is usually <1 µ (Avg. size 200-600nm).

• Methods of preparation include:

• Anti-solvent Precipitation technique - Simple and low cost equipments; but challenge is growing
drug crystals to avoid formation of microparticles. Limitation is that drug needs to be soluble in at
least one solvent and this solvent needs to be miscible with anti-solvent.
• High-shear media milling - Milling chamber charged with milling media, water, drug, and stabilizer is
rotated at very high-shear rate under controlled temp for several days (at least 2–7 days). Milling
medium is composed of glass, Zirconium oxide, or highly cross-linked polystyrene resin.

• High-pressure homogenization in water or non-aqueous media - Cavitation forces within particles

are sufficiently high to convert drug microparticles into nanoparticles. Limitation is the need for
small sample particles before loading and several cycles of homogenization are required.

• Nanoedge Technology: Combination of Precipitation and High-Pressure homogenization

 Supercritical Fluid Process
• Supercritical fluids are fluids whose temperature and pressure are greater than its critical temperature
(Tc) and critical pressure (Tp), allowing it to assume properties of both a liquid and a gas.
• At near-critical temperatures, SCFs, are highly compressible allowing moderate changes in pressure to
greatly alter density & mass transport characteristics of fluid that largely determine its solvent power.
• Once drug particles are solubilised within SCF (usually carbon dioxide), they are re-crystallised at
greatly reduced particle sizes.
• Current SCF processes have demonstrated the ability to create nanoparticulate suspensions of
particles 5–2,000 nm in diameter.
• Several methods of SCF processing have been developed to address shortcomings of the method:
Precipitation with compressed antisolvent process (PCA), Solution enhanced dispersion by SCF (SEDS),
Supercritical antisolvent processes (SAS), Rapid expansion of supercritical solutions (RESS), Gas anti
solvent recrystallization (GAS), and Aerosol supercritical extraction system (ASES).
Cryogenic technique
• Cryogenic techniques enhance dissolution rate of drugs by creating nanostructured amorphous drug
particles with high degree of porosity at very low temp conditions.
• Cryogenic inventions can be defined by the type of injection device (capillary, rotary, pneumatic, and
ultrasonic nozzle), location of nozzle (above or under the liquid level), and the composition of
cryogenic liquid (hydrofluoroalkanes, N2, Argon, O2, and organic solvents).
• After cryogenic processing, dry powder can be obtained by various drying processes like spray freeze
drying, atmospheric freeze drying, vacuum freeze drying, and lyophilisation.
• Spray Freezing onto Cryogenic Fluids - drug and carrier (s.a. mannitol, maltose, lactose, inositol, or dextran) are
dissolved in water and atomized above the surface of boiling agitated fluorocarbon refrigerant. Sonication probe
can be placed in the stirred refrigerant to enhance the dispersion of the aqueous solution.
• Spray Freezing into Cryogenic Liquids (SFL) - It incorporates direct liquid-liquid impingement between
automatized feed solution and cryogenic liquid to provide intense atomization into microdroplets and
consequently significantly faster freezing rates. The frozen particles are then lyophilized to obtain dry and free-
flowing micronized powders.
• Spray Freezing into Vapor over Liquid (SFV/L) - Freezing of drug solutions in cryogenic fluid vapours &
subsequent removal of frozen solvent produces fine drug particles with high wettability. During SFV/L the
atomized droplets typically start to freeze in vapor phase before they contact cryogenic liquid. As solvent
freezes, drug becomes supersaturated in unfrozen regions of atomized droplet, so fine drug particles may
nucleate and grow.
• Ultra-Rapid Freezing (URF)
 Micellar solubilization
• Surfactants are molecules with distinct polar & non-polar regions.
• When concentration of surfactant in water exceeds their critical micelle concentration (CMC, which is in the
range of 0.05–0.10% for most surfactants), micelle formation occurs, which entrap the drugs within the micelles.
This is known as micellization. Surfactants reduce surface tension and generally resulting in enhanced solubility
of poorly water-soluble drugs. Surfactant also improves wetting of solids and increases rate of disintegration of
solid into finer particles.
• Commonly used surfactants include polysorbates (Tweens), polyoxyethylated castor oil, polyoxyethylated
glycerides, lauroyl macroglycerides, and mono- and di-fatty acid esters of low molecular weight polyethylene
glycols.
• E.g. of few drugs that used micellar solubilization include glimepiride, glipizide, repaglinide etc.
• Microemulsions on the other hand optically clear, isotropic, thermodynamically stable systems composed of
external phase, internal phase, surfactant and co-surfactant. They also enhance solubilization of drug by micellar
formation.
Change in pH
• For organic solutes that are ionisable, changing the pH of the system is the simplest and most effective
means to increase aqueous solubility.
Salt formation
• Salt formation is frequently performed on weakly acidic or basic drugs.

• Ideal characteristics of salts are that they are chemically stable, non-hygroscopic, dissolve quickly from
solid dosage forms (unless it is formed with the intent to delay dissolution).

• Selection of Salt: For weakly acidic drugs, a strong base salt is prepared such as sodium and potassium
salts of barbiturates and sulphonamides.

• For weakly basic drugs, a strong acid salt is prepared like hydrochloride or sulphate salts of alkaloidal
drugs (Atropine).

• Size of the counter ion influences the solubility of salt forms of the drug. Smaller the size of the
counter ion, greater the solubility of salt.
• Based on the behaviour of inorganic salt in aqueous solutions, they were divided into kosmotropes
(polar water-structure markers) or chaotropes (water-structure breakers).

• Kosmotrope: It is a doubly charged ion (e.g. So4-2) or an ion with a high charge density (e.g. F-). They are
proposed to interact with adjacent water molecules more strongly than with bulk water.

• Chaotrope: It is a large ion with a single charge (e.g. ClO4- or SCN-). They are proposed to interact with
adjacent water molecules less strongly than with bulk water.

E.g. Caffeine solubility of different salts have different effects on

solubility: Added NaClO4 or NaSCN increases the caffeine solubility,
whereas added Na2SO4 or NaCl decreased it and added NaBr did not
show any significant effect.
• Advantages of Salt formation
• Can be effectively applied for solubilization of weak acids and bases.
• Different salts (i.e. caffeine) of the same drug can also be used to generate crystals with different
lattice energies and hence different solubility's.
• Dissolve quickly from solid dosage form (unless it is formed with the intent to delay dissolution).
• Disadvantages of Salt formation
• Solubilization does not always improve the taste. E.g. Potassium salts frequently have an unpleasant
taste and leave a metallic after taste.
• Selection of an appropriate salt is difficult for desired solubility.
• Not feasible to form salts of neutral compounds.
• Salt formed may be hygroscopic, exhibit polymorphism or may have poor processing characteristics.
• Conversion of salt to free acid/base form of the drug on surface of solid dosage form may alter or
retard drug release.
Cosolvency
• Co-solvency: It is defined as the process wherein the solubility of a poorly water-soluble drug can be
increased by the addition of a water-miscible solvent in which the drug has good solubility.
• Solubility of weak electrolytes and non-polar drugs in water can be improved by altering the polarity
of the solvent.
• Co-solvent system works by reducing the interfacial tension between the aqueous solution and
hydrophobic solute.
• By this technique, high drug concentrations in water can be achieved as compared to other
solubilization approaches.
E.g. of aqueous co-solvents include ethanol, sorbitol, glycerine, propylene glycol, PEG 400.
E.g. of non-aqueous co-solvents include glycerol dimethyl ketal, glycerol formal, glycofurol, dimethyl
acetamide.
• Mechanism of Co-solvency
Co-solvency decreases inter-molecular H-bonding interactions of water

Decreases the ability of water to ‘squeeze out’ a non-polar organic solute

Lowers overall polarity of solution (as compared to pure aqueous system)

Favours dissolution of a non-polar solute.

• Few pharmaceutical products that contain co-solvents:

1. Diazepam injection contains 10% ethanol:Propylene glycol
2. Digoxin Injection contains 10% ethanol:Propylene glycol
3. Paracetamol Pediatric elixir
• Advantages of Co-solvency
• Simple and rapid to formulate and produce.
• Co-solvents may be combined with other solubilization techniques and pH adjustment to
further increase solubility of poorly soluble compounds.
• Disadvantages of Co-solvency
• Toxicity and tolerability related with the level of solvent administered has to be considered.
• Uncontrolled precipitation occurs upon dilution with aqueous media. The precipitates may be
amorphous or crystalline and can vary in size.
• Drugs that are extremely insoluble in water do not readily re-dissolve after precipitation from
the co- solvent mixture.
Hydrotrophy
• Hydrotrophy is a solubilisation process, whereby addition of a large amount of second solute, the
hydrotropic agent results in an increase in the aqueous solubility of first solute.

• Hydrotropic agents are ionic organic salts, consisting of alkali metal salts of various organic acids.
Additives or salts that increase solubility in given solvent are said to “salt in” the solute and those salts
that decrease solubility “salt out” the solute.

• Several salts with large anions or cations that are themselves very soluble in water result in “salting in”
of non-electrolytes called “hydrotropic salts”; a phenomenon known as “hydrotropism.”

• Hydrotrophy designate increase in solubility in water due to presence of large amount of additives.

• Mechanism by which it improves solubility is more closely related to complexation involving a weak
interaction between the hydrotrophic agents like sodium benzoate, sodium acetate, sodium alginate,
urea, and the poorly soluble drugs.
• Hydrotropes are known to self-assemble in solution. Wide variety of compounds have been reported
to exhibit hydrotropic behaviour.

• E.g. include ethanol, aromatic alcohols like resorcinol, pyrogallol, catechol, 𝛼 and 𝛽-naphthols and
salicylates, alkaloids like caffeine and nicotine, ionic surfactants like diacids, SDS (sodium dodecyl
sulphate), and dodecylated oxidibenzene.