Stability_Considerations_In_Formulation_Development.ppt

Stability Considerations In
Pharmaceutical Development
Dr. M. S. Nagarsenker
Professor & HOD
Department of Pharmaceutics
Bombay College of Pharmacy, Mumbai

 Stability – Very important attribute
Family
Workplace
National politics
 With respect to frame of conditions

Stability Evaluations
 Integral part of the drug and dosage form
development.
 Giving due importance to stability issues, ICH
has included this aspect in draft guidelines
Q8 on Pharmaceutical development.
 At step 2 of ICH process on Nov 2004

Pharmaceutical Development
The aim of the pharmaceutical development is to
 Design a quality and stable product and the
process to deliver the product in a reproducible
manner.
 Establish specifications and manufacturing control.
 Identify and control factors which prevent risk to
quality and stability of product.

Stability
 Ability of drug substance or drug product to
remain within specification of identity,
strength, purity and quality.
 Comprehensive assessment
 Chemical
 Physical
 Microbiological
 Toxicological

Stability programme
Covers various stages of development of the
products
1. Preformulation and compatibility
2. Preclinical formulation
3. Clinical and NDA formulation
4. Commitment and product monitoring
5. Post NDA change of formulation

New Drug Substance
Stability evaluations start early in drug
development

Stability programme
ICH guidelines give long term, intermediate and
accelerated conditions and time duration for
storage of samples.
Evaluation:
 Chemical tests
Identification, assay and impurity quantification
 Specific physical and performance tests

Stability Evaluation
There should not be significant change in
storage.
 5 % change in initial assay value
 Impurity level above specified limit
 Change in dissolution profile
 Change in physical parameters like
color, odor, particle size
distribution……..

What went wrong
 Why did Norvin capsules (Ritonavir) failed stability
after storage
 Piroxicam, in fine powder, had satisfactory
dissolution profile. But when compressed at high
compression pressure into tablets, D.T. was
unaffected but the dissolution was poor.
 Carbamazepine samples having similar assay value
and particle size distribution had different dissolution
profiles.

Stability Problems
 In the summer of 1998, Norvir semisolid capsule
supplies were threatened by instability.
 Ritonavir – Antiviral agent
 Marketed as oral liquid and semisolid
Capsules in 1996 for treatment of AIDS
 Ethanol based products
 In mid 1998, several lots were failed stability
dissolution
 Due to change in physical state of drug - form II
crystallization which was 400 times less soluble

 Whether physical state of drug is affected by
storage conditions?
 Whether physical state of drug is affected by
excipients and process?
 Can such change affect dissolution and
chemical stability?
 Can it be controlled?

Active Pharmaceutical
Ingredient
 Physical properties can influence the
performance, stability and manufacturability.

Physical states of drug
substance
 Crystalline systems
polymorphs
 Amorphous systems
 Hydrates
 Solvates

Stability_Considerations_In_Formulation_Development.ppt

Polymorphs
 Polymorphs- Same chemical compound.
 Differ in internal solid state structure.
 Possess different chemical, physical, kinetic,
interfacial properties.
 Have direct impact on quality, dissolution and
stability.
 Unexpected appearance of polymorph can
lead to serious problems.

Polymorphs
 Vapor pressure diagram
 DSC thermogram / thermogravimetry / DTA
scans
 X-Ray diffractogram - means to establish the
polymorphic identity
 Microscopy – Polarizing Optical Microscopy,
Hot stage / Thermal microscopy
 Raman Spectroscopy
 Intrinsic dissolution rates

Intrinsic dissolution studies
 Intrinsic dissolution rates (IDR) for the various polymorphs of
Alprazolam at two different spindle speeds
Crystalline
form
IDR, 50 RPM
(µ/min.cm2)
IDR, 75 RPM
(µ/min.cm2)
Form I 15.8 21.8
Form II 18.4 21.9
Form V 20.7 27.3

Equilibrium solubility of
Phenylbutazone polymorphs at
ambient temperature.
Solvent systems Solubility (mg/ml)
A B C D E
pH 7.0 phosphate
buffer
4.80 5.10 5.15 5.35 5.9
Above buffer with
0.05%Tween 80
4.5 4.85 4.95 5.10 5.52
First buffer with
2.25% PEG 300
3.52 5.77 5.85 6.15 6.72

Dissolution Profiles
P. V. Allen et al, J. Pharm. Sci., 67, 1087 (1978)

Dissolution and Bioavailability
 ‘Physical state’ has direct effect on solubility
of solid, dissolution rate and hence
bioavailability.
 Capsules containing anhydrous Ampicillin
administered to human volunteers, showed
higher Cmax , lower Tmax when compared to
capsules containing Ampicillin trihydrate.

Stability Considerations: API
 An important aspect of early drug product
development is a choice of solid state of drug
which can provide optimal stability as well as
bioavailability.
 Processing of crystalline salts like milling,
polymer coating
 Exposure of drug to elevated temperature
and RH
 Plasticization by water

Case Study I
Sodium Indomethacin (NaIMC) salt with higher
solubility.
Water absorption study at different % RH.
Quantities of degradation products of hydrolysis
5-methoxy-2-methyl-3-indol acetic acid.
Powder X Ray Diffraction study.
P. Tong, AAPS Pharm SciTech 2003, 5(2) Article 26

 Water vapor sorption isotherms at 30º

Powder X- Ray diffraction studies
 No crystallinity at 21%RH in 56 days
 Crystallization at 56%RH, 83%RH

Chemical Stability
The relationship between chemical degradation and crystallinity at
different RH as a function of temperature on Day 15

Conclusions
 Amorphous state upon exposure to %
humidity above critical RH can get converted
into crystalline form- (unknown forms).
 This can result in inferior dissolution patterns
and reduce bioavailability.
 Amorphous forms below critical RH becomes
chemically unstable particularly at high
temperatures.

 Phase transformation can be controlled by
using larger crystals, low humidity and storing
at low temperature.

Development of dosage
form
 Studies be consistent with their scientific purpose and
stage of development of the product
 Level of knowledge gained and not the volume of data
is important
 At a minimum, those aspects of drug substance,
excipients and process, which are critical / present risk
to product stability should be identified and discussed.

Formulation Development
Excipient selection and formulation process:
 Can influence solid state of drug.
 Hence can influence stability, dissolution rate
and availability.
 Can influence intended functionality during shelf
life.
Information on process parameters and
formulation design generated during
development can be utilized to minimize phase
transitions in formulation.

Screening of Drug Excipient
Compatibility
 By evaluating 1:1 mix of drug and excipient at
isothermal storage conditions.
 Evaluation of 1:1 drug excipient mix by
thermal studies like DSC, TGA.

While designing formulation it is important to
know-
 which physical forms of drug exist at different
stages and after the product is stored in final
form.
 How the changes can affect product
performance and stability.

Case study II
Nitrofurantoin
Anhydrous – α and β
Monohydrate – I and II
Excipients:
L- hydroxy porpyl cellulose (grade LH 21)
Lactose monohydrate (Pharmatose 200)
Pregelatinised starch (Starch 1500)
Silicified MCC (Prosolve SMCC 50)
1:1 mix of drug and excipient moistened with
measured amount of water
S.Airaksinen, AAPS Pharm.Sci. Tech. 2005

 Water sorption study
After tray drying and vacuum desiccation
 X- Ray powder diffractometry
 Near IR Spectrometer

 Lactose monohydrate (Pharmatose 200)-
crystalline, minimal water absorbing potential
was unable to control hydrate formation.
 Silicified MCC (Prosolv SMCC 50) -
partially crystalline, hygroscopic was able to
hinder the transformation at low water
content due to porous structure.

 Modified starch (Starch 1500)-
 Amorphous
 Hygroscopic
 Hindered transformation of higher water than
SMCC.
 L HPC (LH- 21):
 Amorphous more effective in controlling the
transformation.
 Both have stronger affinity for water, improved
drug stability.

 Drying-
Critical step in many pharmaceutical processes.
Lactose formulation had higher amounts of
Nitrofurantoin monohydrate followed by
SMCC formulations.
 L-HPC formulations had lowest drug in
crystal form.
 Starch granules gelatinized and retained drug
crystals.
Influence of process

Specific Tests
Formulation attributes
 pH
 Osmolarity
 Ionic strength
 Lipophilicity
 Dissolution testing and
disintrgration as
evaluation parameters
 Redispersion
 Reconstitution
 Particle shape
 Aggregation
 Size distribution
 Rheology
 Globule size
 Creaming/cracking

Container- Closure System
Selection-
stability of drug product
Protection Compatibility safety
 Suitability for storage and transportation
 Dosing device - Accuracy

Formulation Development
Summary
Quality needs to be built in products
 Correct selection of drug substance
 Excipients
 Container closure systems
 Manufacturing process
All these components influence and hence
should be controlled for stability of product
during shelf life.

Stability_Considerations_In_Formulation_Development.ppt

More Related Content

Similar to Stability_Considerations_In_Formulation_Development.ppt (20)

More from Ravi Kumar G (6)

Recently uploaded (20)

Stability_Considerations_In_Formulation_Development.ppt