Post on 07-Mar-2018
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
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
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
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