2-5.

Formulation Development
Issues: Solid Orals
Satish Mallya
January, 2011

Goal
Innovator QTPP

Generic QTPP

Develop a stable, bioavailable, clinically

relevant formulation

Develop a stable, essentially similar

formulation, bioequivalent to the
innovator product

Commence PD from basics

Information on formulation ingredients,

strengths, presentations and storage
conditions available prior to PD

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Critical Parameters
Solubility of API (BCS)

Excipient compatibility
Influence of raw material variability on dissolution
Impact of granulation process on dissolution and
homogeneity
Moisture content of granules after drying
Influence of compression force on dissolution.

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Optimization Studies
Studies are undertaken to optimize:
quantity of binder
quantity of disintegrant
LOD

Different trial batches having varying amounts of disintegrant and binder are
used;
Results of granule flowability, tablet characteristics and comparative dissolution
profiles are compared;
Granules with different LOD levels are compressed and results with respect to
flowability and tablet characteristics are used to finalize formulation;
The formulation so developed is considered to be optimized when there are no
problems (e.g. capping) and the dissolution profile matches the innovator product

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Single API- IR
Ingredient

% per tablet

API

50

Lactose

25

Mag. stearate

0.25

MCC

20.75

Croscarmellose sodium

Mag Stearate

1.0

Coating

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Coating Agent

10

Purified Water

90

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Flow Chart
API
Filler

screening

Mixing of
granulation blend

Binder(s)

Preparation of
binder solution

Granulation
Drying

LOD

Milling

Disintegrant

screening

Initial Blending

lubricant

screening

Final Blending

Compression

Film Coating of Tablets

Solvent
Film coating agent

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Preparation

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Packaging
and Labelling

Weight
Hardness
Friability

Single API- IR
Steps in PD
API is characterized;
Qualitative formulation is developed and each excipient is selected for its intended use
based on optimization studies;
Dry granulation process is generally preferred as the manufacturing process as this
involves less unit operations;
All the critical steps of the manufacturing process are optimized;
Analytical methods are developed and validated for determination of assay, related
substances and analytical method for dissolution testing of the tablets;
The packaging system is chosen and development batches are tested for stability;
Bioequivalence study is undertaken with the comparator product as reference;
For innovator products: if market formulation is not identical to the formulation used in
phase III (pivotal) clinical studies comparative dissolution profiles may be required to
establish equivalency of formulations (f2).

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Single API-IR
API characterization studies
API exhibits polymorphism and exists in two forms - low melting form and high
melting form;
DSC spectra are compared with the information available in literature and found
to be matching with e.g. high melting form;
Thermograms from various API batches exhibit endotherm at an identical
temperature - confirmation that the synthetic process consistently produces the
high melting form;
Different batches of API are tested for:
particle size distribution
flow properties,
bulk density and tapped density

If the API degrades by hydrolysis residual moisture in the tablet can induce
degradation - wet granulation technique may not be suitable.

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Single API-IR
Preformulation Studies
Pre-formulation studies are conducted using the API and commonly
used formulation excipients;
These excipients may be chosen on the strength of previous
experience with manufacturing of this type of solid oral immediate
release dosage forms;
A physical compatibility study is undertaken to determine the
interaction of API with various excipients. The excipients and drug
admixtures in specified ratio are stored e.g. for four weeks at
40C/75 % RH and at 50C/ambient humidity and periodically
checked for any change in physical appearance.

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Single API-IR
Dissolution

If more than 85% of the drug is released within 15 min. in 0.1 N

HCl, pH 4.5 acetate buffer and pH 6.8 Phosphate buffer dissolution
profiles may be accepted as similar without any further
mathematical (f2) calculations;
The discriminatory power of the dissolution method is established;
Comparative in vitro profiles are generated with comparator
product.

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Single API-IR
Development Strategy
Direct compression may not be suitable if API exhibits poor flow
properties;
If the API degrades by hydrolysis wet granulation may not be an
option since the residual moisture in the tablet can induce
degradation;
Dry granulation method may be explored, as it requires lesser unit
operations - roller compactor may be used for preparing compacts;
Various experiments are performed to optimize quantities of
excipients:
disintegrant, diluent and lubricant concentrations;
removal of incompatible excipients

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Single API-IR
Development Strategy
Impact on other process parameters:
Blend uniformity
Compaction process
Compression process
Rotation speed
Uniformity of weight,
Hardness,
Thickness,
Friability,
Disintegration time,
Dissolution.
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Single API-IR
Development Strategy
Container Closure Systems & Stability studies:
HDPE bottle pack/Blister strip pack (choice based on innovator
presentations)
Moisture permeation studies
Results of photostability testing, accelerated stability testing
(40C / 75 % RH) and long-term stability (30C / 75 % RH) used
to justify choice of the packaging materials.

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Coating
Reasons for coating:

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to cover unpalatable taste of the cores

to facilitate swallowing
non functional coating
moisture or photo sensitive API: tablets may be coated with an
agent to provide moisture barrier (e.g. translucent grade of
opadry AMB) [AMB = aqueous moisture barrier] or an
opacifying agent (deemed to be functional coating)

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Coating
Coating by spraying:
using organic solvents (e.g.isopropyl alcohol, methylene
chloride)
as aqueous solution
relevant quality parameter of the coated tablets is dissolution of
the APIs if there are no significant differences, aqueous
coating may be preferred due to environmental reasons and
cost.

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Coating
Parameters for coating:
Weight gain during coating,
Amount of solids in the coating dispersion,
Distance between spray gun and tablet bed,
Spray rate and pattern,
Spray atomizing pressure,
Pan Speed,
Inlet air temperature,
Inlet and outlet air flows,
Tablet-bed temperature,
Homogeneity of coating.

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2 FDC

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Ingredient

% per tablet

API 1

40

API 2

20

MCC

35

Sod. Starch Glycolate

Colloidal Silicone Dioxide

0.3

Mag. Stearate

0.7

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Key Parameters

Stability of the APIs under stress conditions;

Compatibility of the APIs with each other and with the excipients;
Dissolution of both APIs;
Content uniformity of the mixture of APIs with the excipients
Polymorphic changes of the APIs in the FPP.

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Challenges
Stress testing:
Both APIs degrade under different stress conditions

Flowability:
May be excellent for one API but may be good or even poor for other API

Powder densities (bulk and tapped):

API 1: fair compressibility (Hausner factor NMT 1.15)
API 2: passable compressibility (Hausner factor NMT 1.25)

Hygroscopicity:
Both APIs non hygroscopic, but one API forming lumps at high humidity

Particle size analysis:

Not critical if both APIs are soluble

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Conditions
For compatibility of mixture of APIs, only those stress factors may be selected at
which both API1 and API2 are stable during stress testing:
API 1 - unstable under oxidation and base
API 2 unstable under UV light and temperature
Stress

Time

Humidity 75% RH

10 days

Acid 2M HCl

10 days

Photolysis

Visible light : 1.2

million lux hours

If incompatibility is not observed at any investigated condition, a monolayer tablet

is possible.

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Optimization of disintegrant content

Dissolution:
3% sodium starch glycolate (pH 1.2)
API 1: 88.4 %
API 2: 90.2%
4 % sodium starch glycolate (pH 1.2)
API 1: 94.0 %
API 2: 94.5 %
8 % sodium starch glycolate (pH 1.2)
API 1 : 86.7%
API 2 : 88.3 %

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optimum

Other Considerations
Formulations used for biostudy and for marketing are identical;
Pilot batches are manufactured by a procedure fully representative
of and simulating that applied to production scale batch;
Dissolution profiles of comparator & test products are comparable;
Scoreline content uniformity of halves (both APIs).

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Bilayered Tablets
Major issues:
Selection of manufacturing processes for granules in both
layers;
Adjustment of tablet weight -individual layers could be large;
Possible scale-up issues reformulation may be preferred over
change of tooling, if scale-up unsuccessful;
If reformulation required, should one or both layers be
reformulated?
Optimization of formulation and manufacturing process
Disintegrant and lubricant levels
Blending time and moisture content of final blend
Tablet hardness

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January
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Satish Mallya January

Bilayered Tablets
Major Issues:
Essential to establish uniformity of distribution within and
between batches
Determination of content on a mixed sample may not
provide assurance of uniform distribution between individual
units
Content uniformity in the FPP specifications may be the
best solution
Selection of dissolution method and medium
Scoreline and divisibility studies - may not be necessary if
SmPC indicates score line is only to facilitate breaking for ease
of swallowing and not to divide into equal doses.

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3 FDC

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Ingredient

% per tablet

Ingredient

% per tablet

API 1

20.5

API 3

4.2

API 2

27.5

MCC

7.8

MCC

21.6

Lactose

6.8

Sod. Starch Glycolate

4.0

Sodium Starch Glycolate

0.45

Purified water

qs

Mag. stearate

0.05

Ingredient

% per tablet

Sodium Starch Glycolate

1.8

MCC

4.1

Talc

0.2

Magnesium Stearate

1.0

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3 FDC
Compatibility of APIs and between APIs and excipients;
Direct compression of 3 APIs with excipients may result in poor flowability;
If one API is susceptible to hydrolytic degradation in aqueous environment direct
compression may be necessary for that API and wet co-granulation of the
remaining APIs;
The excipients chosen may be similar to those contained in respective single
innovator products;
Overages may be necessary due to complicated manufacturing process;
Challenges with selection of dissolution media;
Comparative dissolution profiles with respective to individual comparator
products, in three media

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Satish Mallya January 20-22, 2010

Thanks