Sponsored by
REMODELED RECRYSTALLIZATION KINETICS TO PREDICT THE PHYSICAL STABILITY OF
POLYMERIC AMORPHOUS SOLID DISPERSIONS
X. Feng1, S. Shah1, M. Rahman2, Z. Y. John Lian3, T. Durig3,D. Tewari3, V. Bi3, S. Majumdar 1, M. A. Repka1
1Department Of Pharmaceutics, School Of Pharmacy, University Of Mississippi, University, MS 38677, USA
2Ashland Specialty Ingredients, Solubilization Center Of Excellence, Columbia, MD 21044, USA
3Ashland Specialty Ingredients, Wilmington, DE 19808, USA
OBJECTIVE
 The assumption that nucleation rate is constant in the Avrami
model leads to an overprediction of 𝛼 𝑡 . An improved kinetics
model is proposed such that the nucleation rate is proportional to
the amorphous fraction:
𝛼 𝑡 =1−
Eq. 2 ) ; 𝑘 = 𝑘0 𝑒𝑥𝑝
Δ𝐸
− 𝐴
𝑅𝑇
( Eq. 3 )
 The DSC measures enthalpy associated with the melting of
crystals during heating and this enthalpy is proportional to the
crystallinity of the sample.
METHODOLOGY
Thermal studies : DSC was utilized to measure the melting
enthalpy of the solid dispersion. Sample were weighed ( 3-5 mg)
in an aluminum sample pan and hermetically sealed at each time
point using a heating rate of 20℃/min from −40℃ to 180℃
( Perkin Elmer, Diamond DSC). The nitrogen purge rate was
20ml/min. An empty pan was used as reference.
Stability Conditions: Amorphous solid dispersion with different
polymer content ( 13,15,17% PlasdoneTM K-29/32 povidone )
were stored in glass vials at different RH(10,40,50%RH/72℃)
and different temperature( 67,70,72℃/50%RH ).
-11.1
14
-11.2
-11.3
-11.5
-11.6
8
0%
10%
20%
30%
40%
50%
60%
28.9
29
Relative Humidity ( % )
Fig. 2: Measurement of recrystallization from
solid dispersion(85%EFV:15% Plasdone TM K29/32 povidone @72℃/10%RH)
Fig. 1: Evaluating the recrystallization rate
using DSC
Comparison of Avrami equation and
improved kinetic model
1
1
0.8
0.8
0.6
0.6
0.4
0.4
Improved Model, 17% PlasdoneTM K-29/32 povidone
Improved Model, 15% PlasdoneTM K-29/32 povidone
0
0
Improved Model, 13% PlasdoneTM K-29/32 povidone
Improved model
Avrami Equation
Experimental data
0.2
50
100
150
Experimental, 17% PlasdoneTM K-29/32 povidone
0.2
Experimental, 15% PlasdoneTM K-29/32 povidone
Experimental, 13% PlasdoneTM K-29/32 povidone
0
0 250
200
50
Time ( hours )
Fig. 3: Experiment data fitting to the Avrami
equation and the improved model
Influence of polymer content on
recrystallization rate constant
 The presence of PVP significantly
decreased the recrystallization rate
constant which might be attributed to
the higher ratio efavirenz trapped
into polymer matrix and higher
energy required to nucleate ( Fig. 4 ).
 The Tg of the PlasdoneTM K-29/32
povidone and efavirenz are 174 ℃
and 33 ℃ respectively. Solid
dispersion’s Tg increased as the
polymer content increased.
16
10
α( t )
𝛼 𝑡 = 1 − exp(−𝑘𝑡 ) ( Eq. 1) is most commonly used.
y = -1.3806x + 29.029
R²= 0.9507
-11
-11.4
1
0.8
0.8
Improved Model, 10% RH
Improved Model, 40% RH
Improved Model, 50% RH
0.4
0.6
Improved model, 67°C
Improved model, 70°C
Improved model, 72°C
Experimental, 72°C
Experimental, 40% RH
Experimental, 70°C
0.2
Experimental, 50% RH
0
0
50
100
Time ( hours )
Fig. 5: Influence of relative humidity on
recrystallization rate constant
Experimental, 67°C
150
0
0
200
50
250
100
Time (hours)
Fig. 7: Recrystallization rate constant as a
function of relative humidity for
85%EFV:15% Plasdone TM K-29/32
povidone @72℃
29.1
29.2
29.3
29.4
29.5
1/T X1000 (1/K)
Fig. 8: An Arrhenius plot of crystallization
constant as a function of temperature for
85%EFV:15% Plasdone TM K-29/32
povidone @50%RH
Influence of relative humidity on recrystallization rate constant
 Linear regression of the experimental data showed that k
increased linearly with RH in the range used in this study( Fig. 5
and Fig. 7 ). The rate increase might be attributed to the waterinduced plasticization.
Influence of temperature on recrystallization rate constant
 The recrystallization rate increased exponentially with
temperature( Fig. 6 and Fig. 8 ). Solving the relationship between
k, T, ∆𝐸𝐴 allows the prediction outside experiment temperature
range( Eq. 3 ).
200
250
CONCLUSION
0.4
Experimental, 11% RH
0.2
150
Fig. 4: Influence of polymer content on
recrystallization rate
1
0.6
100
Time ( hours )
α(t)
𝑛
 Relative crystallinity was used to
evaluate the fraction of recrystallized
∆𝐻(𝑡)
efavirenz. 𝛼 𝑡 =
( Eq. 4 )
Δ𝐻∞
 ∆𝐻∞
is the maximum melting
enthalpy for a certain temperature
and RH. 𝛼 𝑡 varies from 0-1 ( Fig. 1
and Fig. 2 ).
 The experimental data were fitted
into the improved equation by a
multivariate nonlinear regression
method using Matlab ( Fig. 3 ).
 All correlation coefficients, r2 from the
improved model were larger than the
Avrami equation’s r2. .
 Improved model provided better fit
than the Avrami equation, especially
in secondary crystallization ( Fig. 3 ).
y = 19.638x + 7.4938
R²= 0.9492
12
α(t)
 Polymeric solid dispersions prepared by different techniques such
as spray drying are widely used to enhance the physical stability of
amorphous drug substance as this formulation improve the
solubility and bioavailability of BCS class-2 drug. However
amorphous systems are unstable from the thermodynamic view.
Recrystallization is inevitable which will influence the dissolution
rate and might result in changes in in vivo drug delivery. Several
theoretical kinetics models were proposed to describe the
recrystallization kinetics, among those Avrami equation:
Using DSC to determine the
recrystallization rate
α(t)
INTRODUCTION
18
Ln(K)
 To utilize an improved Avrami equation to predict the
recrystallization
rate
of
efavirenzpolyvinylpyrrolidone( PlasdoneTM K-29/32 povidone, PVP )
solid dispersions.
RESULTS AND DISCUSSION
-10.9
𝐾×105
 To understand how factors such as temperature, relative
humidity and polymer content influence the recrystallization
behavior of drug-polymer solid dispersion system.
1
(
1+𝑘𝑡 𝑛
-10.8
20
150
Fig. 6: Influence of temperature on recrystallization
rate constant
 The improved kinetic model provides a more accurate description of
EFV/PVP amorphous solid dispersion’s recrystallization.
 Temperature, relative humidity and polymer content are main factors
influencing the recrystallization kinetics.
 The PlasdoneTM K-29/32 povidone can significantly inhibit the
recrystallization rate of the amorphous solid dispersion.
 By fitting the data to the improved model, the recrystallization rate
constant can be found outside of the experimental temperature range
(e.g. room temperature), which is helpful to predict the
recrystallization kinetics.
200
250
ACKNOWLEDGMENT
The authors would like thank the Pii Center for Pharmaceutical Technology for its
assistance with this project.