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
3
Mag Stearate
1.0
Coating
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Coating Agent
10
Purified Water
90
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Flow Chart
API
Filler
Binder(s)
screening
Mixing of
granulation blend
Preparation of
binder solution
Granulation
Drying
LOD
Milling
Disintegrant
screening
lubricant
screening
Initial Blending
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
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;
 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:
–
–
–
–
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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
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 %
• 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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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