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Estimation of thermal degradation of cellulose esters during thermal processing
12th September 2012
Hrushikesh Karandikar
www.pharmaceutical-engineering.brad.ac.uk
Aims and Objectives• To understand pharmaceutical formulation challenges associated
with thermal process, hot melt extrusion (HME).
• To analyse the chemical stability of polymers during HME
processing .
• Estimation of thermal degradants of cellulose esters by HPLC
method.
• Application of QbD concept for HPLC method development and
validation.
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Thermal process: Hot melt extrusion (HME)
Courtesy: http://www.rottendorf.de/index.php/hot-melt-extrusion.html
Excipient/ polymers
Excipient/ polymersDrugDrug
. .............. . . . .........
. .............. . . . .........
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Pros Cons
Solvent free, short processing time API/Polymer instability, impuritiesdue to degradation
Robust, continuous and economic Requires high energy input
Reduced number of unit operation cannot apply to heat-sensitivematerials
HME process
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Excipients / Polymers
• Excipients definition and purpose
• Major portion of formulation and its impact on formulation.
• Need due consideration for successful formulation
• Recent regulatory aspects and regulatory pressures over industries. *
• Limited availability of pharmaceutical polymers for innovative techniques
such as HME, injection moulding. **
• Suitability of well established polymers for these techniques.
* http://www.expresspharmaonline.com/20110215/market03.shtml**Sandeep Singhal et al (2011), Hot Melt Extrusion Technique, WebmedcentralPharmaceutical Sciences.
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Cellulose ester derivatives: HPMCAS and HPMCPHydroxy propyl methyl cellulose acetate succinate (HPMCAS), and Hydroxy propyl
methyl cellulose phthalate (HPMCP) have following applications in the
pharmaceuticals
1. Conventional Aqueous Dispersion Coating
2. Dry coating
3. Solid dispersions
Phthalic acid
Hydroxy propylmethyl cellulose acetatesuccinate (HPMCAS)
Hydroxy propylmethyl cellulosephthalate (HPMCP)
Acetic acid, succinic acid
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Major Concerns related to this discussion
• Degradation of excipients during hot melt extrusion process.
• The release of acetic acid (AA), succinic acid (SA) or phthalic acid
(PA) can affect pH of formulations consequently altering product
quality and its performance.
• Quantification of extruded excipients’ associated impurities.
• HPLC method development and validation through the principles
of QbD supporting regulatory requirements
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Robustness(Change in pH,
Temperature, Flow rate)
Ruggedness(Analyst, different days, Column set)
Product and process understanding and control
HPLC based separation of thermally extruded products
STEP 2: EXPERIMENTAL DESIGN
STEP 3: FINAL METHOD
SELECTION
STEP 4: RISK ASSESSMENT
STEP 5: METHOD PERFCONTROL
STRATEGYORMANCE
STEP 1: METHOD INTENT
C-18 ColumnpH=3Phosphate
Buffer
4 mobile phases with 2
buffers
2 Columns
3 pH values
Optimization of method
Resolution of peaks
Retention time
Peak properties
System suitability, robustness,
degradation analysis
Data base review and method development
suggestion
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Effect of different buffers with solvents
Potassium dihydrogen phosphate buffer
Sodium dihydrogen phosphate monohydrate
Sodium dihydrogen phosphate dihydrate
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Effect of different columns and flow rates
Potassium dihydrogen phosphate buffer and methanol combinationwith C-8 column
Potassium dihydrogen phosphate buffer and methanol combination with C-18 Column at flow rate 0.9mL/min
Potassium dihydrogen phosphate buffer and methanol combination with C-18 Column at flow rate 1.1mL/min
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Effect of pH of mobile phase
Phosphate buffer, pH= 3.0
Phosphate buffer, pH= 5.0
Acetic acid
Succinic acid
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Robustness(Change in pH,
Temperature, Flow rate)
Ruggedness(Analyst, different days, Column set)
Product and process understanding and control
HPLC based separation of thermally extruded products
STEP 2: EXPERIMENTAL DESIGN
STEP 3: FINAL METHOD
SELECTION
STEP 4: RISK ASSESSMENT
STEP 5: METHOD PERFCONTROL
STRATEGYORMANCE
STEP 1: METHOD INTENT
C-18 ColumnpH=3Phosphate
Buffer
4 mobile phases with 2
buffers
2 Columns
3 pH values
Optimization of method
Resolution of peaks
Retention time
Peak properties
System suitability, robustness,
degradation analysis
Data base review and method development
suggestion
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The knowledge based approach helped in better
understanding of the factors influencing
chromatographic separation.
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Method developedMobile phase: Phosphate buffer (pH=3) and methanol, gradient approach. C-
18 Column.
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Need Validated method?
Then why?
• Validation confirms performance capabilities of methods.
• Formulation decisions based on the analytical results.
• Trust on method and faith on the results.
• Confidence window and reliability of method
Just for regulatory requirements and for approvals?
NO!
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Name SystemSuitability
Theoreticalplates
Tailingfactor
AA 0.3026 4096 1.20SA 0.4040 3226 1.10PA 0.8040 5323 1.15
USP criteria
≤ 2.0% RSD ≥ 2000 ≤ 2.0
Validation parameter: Method Selectivity and system suitability
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Linearity and LOD ,LOQ determination
Name Linearity R²
LOD(µg/mL)
LOQ (µg/mL)
AA 0.9997 4.07 12.338SA 0.9995 5.51 16.72PA 0.9988 1.741 5.275
y = 478.2488x - 1181.8694R² = 0.9995
0.0020000.0040000.0060000.0080000.00
100000.00120000.00140000.00160000.00
0.000 100.000 200.000 300.000 400.000
Are
a
Concentration (µg/mL)
Linearity of Succinic Acid
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Robustness : Change in flow rate
High flow: 1.1 mL/min
Low flow: 0.9 mL/minName High
FlowLow Flow
AA 0.3267 0.2498SA 0.3999 0.3367PA 0.2780 0.8968
USP criteria
≤ 2.0% RSD
≤ 2.0% RSD
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Robustness : Change in pH
Name High pH Low pH
AA 0.2009 0.4757SA 0.1844 0.3754PA 0.1098 0.1590
USP criteria
≤ 2.0% RSD
≤ 2.0% RSD
High pH: 3.1
Low pH: 2.9
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Name Recovery 1
Recovery 2
Recovery3
AA 99.71% 99.12% 101.19%SA 103.56% 98.85% 101.56%PA 100.56% 101.35% 100.28%
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• The simple RP-HPLC method is developed, validated.
• This method can be suitable for deciding limits for possible excipients/API
interactions in a drug formulation through HME.
• It has potential for estimation of known and unknown impurities
simultaneously
• Critical parameters required for chromatographic separation + greater
confidence in the methods = supports potential regulatory concerns
Conclusion
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