XRPD Line Broadening Analyses to
Study Micronization Induced Disorder
and Environmental Annealing
Glenn Williams, Jeff Brum, Rachel Forcino,
Fred Vogt
GlaxoSmithKline
Why Study Micronization Induced Disorder?
Milling
Non-Micronized
Micronized
Process of micronization results in significant attrition with consistent
micron size particles, but the high energy process may also induce an
element of “disorder” in the material.
While this process improves dissolution and particle uniformity of the
API the resulting “disorder” may affect stability and physicochemical
properties, ultimately with a potential effect on dissolution and particle
uniformity??
Micronization Mill
Changes in Physical Properties
Sample: GW786034B_K074440_DSC
Size: 2.5840 mg
Method: DSC_GW786034
Comment: EE176981
File: I:...\GW786034\GW786034B_K074440_DSC.001
Operator: RGF
Run Date: 07-Jun-2007 14:06
Instrument: DSC Q1000 V9.0 Build 275
DSC
Sample: GW786034B (Pazopanib) Bx 108001
Size: 4.1240 mg
Method: STANDARD DSC METHOD
Comment: Top of keg. Keg 2 of 8
File: I:...\GW786034B\108001 TOP KEG DSC.001
Operator: COF
Run Date: 16-Sep-2010 16:58
Instrument: DSC Q2000 V24.2 Build 107
DSC
0.0
Surface Area
-0.08
-0.10
Heat Flow (W/g)
Heat Flow (W/g)
-0.1
-0.2
-0.3
-0.12
Surface Energy
-0.4
-0.14
-0.5
180
Temperature (°C)
Exo Up
Sample: GW786034B_K074440
Size: 27.5940 mg
Method: Standard Method
Comment: EE176981
80
Universal V4.2E TA Instruments
File: I:...\GW786034\GW786034B_K074440_TGA.001
Operator: MB
Run Date: 07-Jun-2007 15:47
Instrument: TGA Q500 V6.3 Build 189
TGA
105
0.6
100
Weight (%)
0.4
90
0.2
Deriv. Weight (%/°C)
95
100
120
Crystallinity
XRPD
85
140
160
180
Temperature (°C)
Exo Up
Sample: GW786034B Ball Milled
Size: 10.3660 mg
Method: Standard Method
Comment: Ball Milled
200
Universal V4.2E TA Instruments
File: GW786034B_US061115667_BALLMILLED_TGA.001
Operator: BL
Run Date: 01-Jun-2006 10:48
Instrument: TGA Q500 V6.3 Build 189
TGA
100
0.6
95
0.4
90
85
0.2
Deriv. Weight (%/°C)
130
Weight (%)
80
80
80
0.0
75
0
50
100
150
Temperature (°C)
200
250
300
Universal V4.2E TA Instruments
Thermal
DSC, TGA
0.0
75
70
0
50
100
150
Temperature (°C)
200
250
300
Universal V4.2E TA Instruments
Moisture Sorp.
GVS
Are we investigating all the possible changes that may occur and the
impact of those changes on the final formulation/processing and product?
“Disorder”?
Crystal “healing” or environmental “annealing” is often observed in
aged/environmentally exposed materials
Aging - API “hold times”
Determination of the true contributions/components of disorder is
necessary to understand and predict the effects on physicochemical
properties and pharmaceutical processing
Thermal Analysis Comparison of Milled API
2
-0.85
Micronized
0
-0.90
Ball milled
-2
-0.95
180.01°C
Ball milled
-4
-6
-100
-1.00
175.36°C(I)
0
100
200
Temperature (°C)
Exo Up
Heat Flow (W/g)
Heat Flow (W/g)
158.83°C
300
-1.05
400
Universal V4.2E TA Instruments
Tg
Tg of amorphous standard higher than exotherm in micronized API
Surface vs Bulk Amorphous
Wu, T.; Sun, Y.; Li, N.; de Villiers, M.; Yu, L. Langmuir 2007, 23,
5148
Lei Zhu & Janan Jona & Karthik Nagapudi & Tian Wu Pharm Res
(2010) 27:1558–1567
Sayantan Chattoraj, Chandan Bhugra, Chitra Telang, Li Zhong and
Zeren Wang, Changquan Calvin Sun. Pharm Res, 2012, Volume
29, Number 4, Pages 1020-1032
Amorphous griseofulvin 13C T1 and T1ρ measurements
13C
Melt-quench
(initial)
Melt-quench
(ground)
T1
13C
T1ρ
1.60 ± 0.12 s
78 ± 13 ms
0.74 ± 0.18 s
45 ± 13 ms
Lower 13C T1ρ and T1 values are consistent with higher molecular
mobility in the ground sample
Variable temperature measurements were not performed because of
“ground” sample instability – recrystallization occurs rapidly under
MAS spinning conditions
Griseofulvin 13C CP-TOSS spectra
13C
CP-TOSS spectra
Micronized API(red trace) shows the signature of amorphous
material
Thermal Analysis Comparison of API with
Varied Micronization Energy
0.2
1.0
0.8
0.0
153.49°C
Micronized 60 psi
-0.2
145.68°C
-0.4
0.4
Micronized 20 psi
Heat Flow (mW)
Heat Flow (W/g)
0.6
0.2
-0.6
0.0
-0.8
0
Exo Up
50
100
150
Temperature (°C)
200
-0.2
250
Universal V4.2E TA Instruments
Amorphous component (exotherm) increases with increased
micronization energies
Gravimetric Vapor Sorption
Re-crystallization
Post Gravimetric Vapor Sorption
0.4
034 MICRONIZED dry 20psi rerun 20Feb.001
034 MICRONIZED DRY 20PSI Post GVS RERUN 20FEB.002
0.2
Heat Flow (W/g)
0.0
-0.2
-0.4
Post GVS
-0.6
-0.8
20
Exo Up
40
60
80
100
120
Temperature (°C)
140
160
180
200
Universal V4.2E TA Instruments
After one GVS cycle the re-crystallization event is gone –
consistent with amorphous recrystallization
Separating Components of Disorder
Amorphous
Thermal analysis
GVS-recrystallization
SS-NMR
Nano-crystalline content
XRPD – line broadening
GVS/porosity
Surface area
Why XRPD Line Broadening?
Why study micronized materials by XRPD?
Crystal is essentially a 3D molecular diffraction grating
http://physics-animations.com/Physics/English/DG10/
The Scherrer Equation
K
B 2  
L cos 
Peak width (B) is inversely proportional to the
crystallite size (L)
Short Range vs. Long Range Order
P. Scherrer, “Bestimmung der Grösse und der inneren Struktur von Kolloidteilchen mittels Röntgenstrahlen,”
Nachr. Ges. Wiss. Göttingen 26 (1918) pp 98-100.
XRPD – Particle vs. Crystallite
XRPD – Instrumental Factors
Same sample – Different instrument settings
Need quality and consistent data collection
XRPD – Sample Analysis
Convenient Capillary Analysis Setup
Possible Spinning in
both X-Y and X-Z
planes
capillary
Capillary sample may be loaded into holder (pre-aligned) and analyzed in
standard transmission setup with auto-changer and without need for instrument
reconfiguration to capillary analysis with standard goniometer heads.
XRPD – Sample Analysis – Transmission Setup
Intensity (counts)
Visual Comparison of Raw Patterns
80000
60000
40000
20000
0
5
10
15
20
25
30
35
40
45
50
55
2Theta (°)
Profile Fitting To Obtain FWHM
Counts
x2813a1-RoomTemp
x2813a1 100.0 %
40000
20000
0
10
20
30
40
50
Position [°2Theta]
FWHM
XRPD – Sample Analysis
Non-micronized and freshly micronized materials show significant
differences in linewidth – consistent and suitable for analysis
“Annealing” Studies
Annealing
1. To subject (glass or metal) to a process of heating and
slow cooling in order to toughen and reduce brittleness.
2. To strengthen or harden.
Study 1
Samples of fresh micronized material were equilibrated at 6 different
temperatures. Samples were heated in the DSC cell, in open DSC
pans, and held isothermal for at least 60 min.
Study 1 Results
Linear relationship observed with increasing temperature and XRPD
linewidth (FWHM) – Increase in crystallite size as increase temperature
Environmental “Annealing”
Study 2
Samples of micronized material lot stored at 3 different RHs and at 2
different temperatures. Samples were pulled periodically over a
several week period of time.
LiCl (~10 %)
Ambient
50 °C
NaBr ( ~50 %)
Ambient
50 °C
K2SO4 (~95%)
Ambient
50 °C
Study 2 – Time Course
Within 2 weeks all conditions appear to have reached an equilibrium with
respect to a reduced FWHM
Study 2 – Temperature Humidity Effect
A synergistic effect on annealing is apparent with increased
temperature and relative humidity
Microscope Comparison
Freshly Micronized
“Annealed”
No obvious difference in particles post “annealing” - Consistent with
healing of fractures/fines.
Healing of Fractures
Increase in averaged crystallite size
“Fresh”
“Aged”
“Fresh”
“Aged”
Conclusions
With further study we may be able to better understand “disorder”
generated in micronized API’s and separate the contributions of
true glassy amorphous and nano-crystalline content.
We are currently evaluating the physiochemical changes that are
associated with this observed crystal “healing” - related moisture
sorption, surface area and porosity, thermal, XRPD, and ssNMR
data.
We are applying this same methodology to other projects with
similar observations/results.
Acknowledgements
Jeff Brum
Rachel Forcino
Fred Vogt (SS-NMR)
Robert Carlton (SEM)