2-5.

Formulation Development
Issues: Solid Orals
Satish Mallya

January, 2011
 Goal
Innovator QTPPQuality Generic QTPP
Target
Product Profile
Develop a stable, Develop a stable, essentially
bioavailable, clinically similar formulation,
relevant formulation bioequivalent to the innovator
product

Commence ‫ تبدأ‬PD from Information on formulation

basics ingredients, strengths,
presentations and storage
conditions available prior to PD

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 Critical Parameters

 Solubility of API Biopharmaceutics Classification

System (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;

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 Optimization Studies

 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 3
Mag Stearate 1.0
Coating
Coating Agent 10
Purified Water 90

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 Flow Chart
API
Filler Mixing of
screening
granulation blend

Preparation of Granulation
Binder(s) binder solution

Drying LOD

Milling

Disintegrant screening Initial Blending

lubricant screening Final Blending

Weight
Compression Hardness
Friability
Solvent
Film coating agent Preparation Film Coating of Tablets

Packaging
and Labelling

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 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;

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 Single API- IR
Steps in PD
 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;

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 Single API-IR
API characterization studies
 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 40ºC/75 % RH and at
50ºC/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;

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 Single API-IR
Development Strategy
 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 (40ºC / 75 % RH)
and long-term stability (30ºC / 75 % RH)
used to justify choice of the packaging
materials.

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 Coating

 Reasons for coating:

– 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

Ingredient % per tablet

API 1 40
API 2 20
MCC 35
Sod. Starch Glycolate 4
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 % optimum
• API 2: 94.5 %

– 8 % sodium starch glycolate (pH 1.2)

• API 1 : 86.7%
• API 2 : 88.3 %

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 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;

 Score line – 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
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 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 Product information for health professionals (SmPC
Summary of Product Characteristics ) 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
Ingredient % per Ingredient % per tablet
tablet
API 1 20.5 API 3 4.2
API 2 27.5 MCC 7.8
MCC 21.6 Lactose 6.8
Sod. Starch 4.0 Sodium Starch 0.45
Glycolate Glycolate
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;

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 3 FDC

 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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32 | Satish Mallya January 20-22, 2010
Thanks