Crystallization of Active Pharmaceutical Ingredient

in Drug Product: A Case Study

Wenning Dai

GlaxoSmithKline King of Prussia, PA

2013 AIChE Annual Meeting

Nov 4th, 2013

Outline

Introduction

Drug product formulation

A novel approach to study drug product stability

– Experiments

– Equipment

Results and discussion

Conclusions

Introduction

Crystallization has been widely used in pharmaceutical industry to manufacture active

pharmaceutical ingredients (APIs).

It plays an important role in defining the stability and drug release properties of drug

products.

Over 90% of all pharmaceutical products are formulated in their crystalline solid form.

Crystallization study at API particle forming steps has been well documented.

However, research on drug product stability through crystallization kinetics studies has not

yet been reported.

– In many cases, drug product instability is a result of supersaturation of API

In this talk, I will present a novel experimental approach to study a drug product stability

from crystallization perspective.

– A case study: an eye drop product for treatment of wet age-related macular

degeneration (wet AMD)

Cyclodextrin-Based Eye Drop Formulations

Cyclodextrins (CD) are cyclic

oligosaccharides, having three common

forms (α-, β-, and γ)

Cyclodextrins have been reported to use

for several aqueous eye drop drug

products

They form water-soluble complexes with

lipophilic drugs.

Figure 1. β-Cyclodextrin

Captisol : β-cyclodextrin sulfobutylether

GSK eye drop: cyclodextrin-based formulations

Thorsteinn Loftsson, etc, Acta Ophthalmol. Scand. 2002, 80, 144-150

Background

Precipitation of API solid has been observed in eye drop developmental batches.

Prior knowledge suggested that the eye drop formulations were supersaturated

with regards to API.

Therefore, the understanding of kinetics of the API precipitation in eye drop

formulations is of critical to successful development of eye drop manufacture

processes, packaging and long term stability of the product

Objectives

Confirm supersaturation of API in the eye drop

Understand the metastability of formulations under various environmental

conditions.

Determine the API crystallization kinetics (crystal growth and nucleation)

Obtain insight into the API solid forming mechanism

API Seeding Study

Objective: Confirm API supersaturation, and gain understanding of API crystal

growth kinetics in the eye drop

Procedure: A freshly prepared eye drop solution was stirred at predefined

temperature, and then seed material was charged to the clear solution; an in-situ

transflectance turbidity probe monitored the solution turbidity.

Formulation Captisol Concentration

[mg/mL]

pH Temperature[C] API Concentration

[mg/mL]

Low Strength 70 5.0 5 5

High Strength 90 4.25 5 10

High Strength 90 4.25 25 10

High Strength 90 4.25 40 10

API Nucleation Induction Time Study

Objective: Gain understanding of API nucleation kinetics and their impacts on

drug product stability

Procedure: A freshly prepared eye drop solution was stirred at predefined

temperature. An in-situ transflectance turbidity probe was used to monitor the

solution clarity change (turbidity).

Formulation Captisol Concentration

[mg/mL]

pH Temperature

[C]

API Concentration

[mg/mL]

Low Strength 70 5.0 5 5, 6, 7, 8,10

Low Strength 70 5.0 15 8

Low Strength 70 5.0 25 5, 6, 7, 8,10

Low Strength 70 5.0 40 8

High Strength 90 4.25 5 14

High Strength 90 4.25 15 14

High Strength 90 4.25 25 10, 12, 13, 14

High Strength 90 4.25 40 10, 14

Equipment

A HEL automate was employed for all

the studies.

It had four 100mL glass reactors,

enabling efficient parallel

experimentation.

Each reactor was equipped with a

transflectance which was high sensitivity

for detecting the onset points of

nucleation.

Turbidity and Temperature Profile As a Function of Time

Temperature

Nucleation Induction Time

Eye Drop Turbidity

Growth

Induction time definition: The time elapsed from the creation of the initial supersaturation

to the detection of the first phase separation in the system.1

A. G. Jones, Crystallization Process System, 2002, 131

Results and Discussion: Crystal Growth

Temperature Impacts on API Growth Rate

•Temperature has profound effect on the API crystal growth rate.

• Under the same conditions (seed load, the total API concentration and pH), API

crystal growth rate decreases in the order of 40C, 25C and 5C exponentially.

y = 1.4907e0.111x

R² = 0.9545

0

20

40

60

80

100

120

140

160

180

200

0 10 20 30 40 50

AP

I G

row

th R

ate

(Δ

V/m

in, x

10

5)

Temperature (C)

10 mg/mL API, 9% Captisol, pH 4.25

Temperature Impacts on API Growth Rate (Cont’d)

A plot of ln(G) vs. T-1 gives a linear relationship, indicating the growth kinetics can

be described by an Arrhenius equation,

where G is growth rate, T is temperature,

A and g are constants, EG is activation

Energy, ∆C is supersaturation

R² = 0.9559

-12

-11

-10

-9

-8

-7

-6

-5

-4

0.003 0.0032 0.0034 0.0036 0.0038ln

(AP

I Gro

wth

Rat

e)

(ln

(ΔV

/min

))

Temperature-1 (K-1)

10 mg/mL API, 9% Captisol, pH 4.25

Allan S. Myerson, Handbook of Industrial Crystallization, 2nd Ed, 2002, 33-65

Results and Discussion: Nucleation Induction

Time

API Concentration Impacts on Nucleation Induction Time

• Under the same temperature, both formulations nucleation induction time increases with

decreasing API concentration.

• The relationship between induction time and API concentration can be described by

a power law equation.

y = 11838x-3.952

R² = 0.8388

0

5

10

15

20

25

30

35

4 5 6 7 8 9 10 11

Ind

uct

ion

Tim

e (

hr)

API Concentration (mg/mL)

7% Captisol, pH 5.0, 25C

y = 2E+08x-5.969

R² = 0.9339

0

50

100

150

200

250

9 10 11 12 13 14 15

Ind

uct

ion

Tim

e (

hr)

API Concentration (mg/mL)

9% Captisol, pH 4.25, 25C

Impacts of API Supersaturation on Induction Time

(Con’t)

y = 6E+06x-5.969

R² = 0.9342

y = 133690x-3.946

R² = 0.8397

0

50

100

150

200

250

4 6 8 10 12 14 16 18 20

Ind

uct

ion

Tim

e (

hr)

API Supersaturation (c/c*)

9% Captisol, pH 4.25, 25C 7% Captisol, pH 5.0, 25C

• The nucleation induction time is a function of supersaturation and formulation composition.

• It increase with decreasing supersaturation described by a power law

Nucleation Induction Time Vs. Temperature

•The nucleation induction time is a function of temperature and formulation composition.

• It decrease with increasing temperature described by an exponential expression.

y = 304.38e-0.149x

R² = 0.9039

0

50

100

150

200

250

300

0 5 10 15 20 25 30 35 40 45

NIn

du

ctio

n T

ime

(h

r)

Temperature (C)

8 mg/mL API, 7% Captisol, pH 5.0

y = 1590.2e-0.159x

R² = 0.9845

0

100

200

300

400

500

0 10 20 30 40 50

Ind

uct

ion

Tim

e (

hr)

Temperature (C)

14 mg/mL API, 9% Captisol, pH 4.25

Results and Discussion: API Solid Forming

Mechanism

Polarized Light Microscopy Images

2h, 40C 21h, 40C 4h, 40C

14 mg/mL API, 9% Captisol, pH 4.25

Possible Mechanism for Solid API Solid Formation

The images of microscope of the eye drop formulations suggest that a

second liquid phase (oiling) is formed prior to API crystallisation from this

second phase.

The presence of an oil phase may result in liquid separation instability.

It is hypothesized primarily by the resulting shape of precipitated crystals,

which are formed spherically.

Conclusions

I have presented a novel and simple approach to understand long term

stability of the eye drop (drug product) through API crystallization kinetics

study.

It is revealed that the crystallization in drug product follows the similar

crystallization kinetics as that for pure APIs.

Seeding experiments have confirmed the API concentration in the

formulations is above the solubility limit (supersaturated) through formation of

API-cyclodextrin complex.

Crystal growth rates increase with temperature which can be described by an

Arrhenius type of equation

Because of the supersaturated formulations, we recommended that any API

solid contamination in the final eye drop drug product should be avoided.

Conclusions (Con’t)

The induction time experiment data have shown that all the formulations are

metastable; drug product metastability (long nucleation induction) increases as

with decreasing temperature, API supersaturation, and pH.

Therefore, we recommended the eye drop product should be stored at low

temperature, such as 5C.

The microscopic images of the eye drop formulations suggest that a second

liquid phase (oiling) is formed prior to API crystallization.

Acknowledgements

Mark Strohmeier Global Analytical Sciences

Xiaofeng Zhu Global Formulation Development

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