Estimation of thermal degradation of cellulose esters ... · Estimation of thermal degradation of cellulose esters during thermal processing ... short processing time API/Polymer

www.pharmaceutical-engineering.brad.ac.uk

Estimation of thermal degradation of cellulose esters during thermal processing

12th September 2012

Hrushikesh Karandikar


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.


Thermal process: Hot melt extrusion (HME)

Courtesy: http://www.rottendorf.de/index.php/hot-melt-extrusion.html

Excipient/ polymers

Excipient/ polymersDrugDrug

. .............. . . . .........

. .............. . . . .........


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


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.


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


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


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


Effect of different buffers with solvents

Potassium dihydrogen phosphate buffer

Sodium dihydrogen phosphate monohydrate

Sodium dihydrogen phosphate dihydrate


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


Effect of pH of mobile phase

Phosphate buffer, pH= 3.0

Phosphate buffer, pH= 5.0

Acetic acid

Succinic acid


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


The knowledge based approach helped in better

understanding of the factors influencing

chromatographic separation.


Method developedMobile phase: Phosphate buffer (pH=3) and methanol, gradient approach. C-

18 Column.


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!


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


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


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


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


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%


• 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


Documents

Estimation of thermal degradation of cellulose esters ... · Estimation of thermal degradation of cellulose esters during thermal processing ... short processing time API/Polymer