determination of the absolute amount of low amorphous ...100,+ determination of the absolute amount...
TRANSCRIPT
100,+
Determination of the absolute amount of low amorphous content in commercial inhalation lactose
grades: TAM, DSC and GVS comparedS. Grönberg², A. Shevchenko¹, J. Husman-Piirainen¹, L.-E. Briggner²
¹Global Pharmaceutical Research, Research and Development, Orion Corporation, Espoo, Finland ²Adroit Science AB, Lund, Sweden
Introduction
We addressed the following problems: •Processing destroys crystalline surfaces •Inconsistency in cohesive/adhesive behavior •Manufacturing problems •Absolute amount of amorphous content is unknown
We prove the accuracy and compare the sensitivity of the known methods used for quantification of absolute amorphous content of lactose and search for the most versatile method for industry.
Methods
Partially amorphous alpha-lactose monohydrate was manufactured from crystalline lactose monohydrate (LMH). We have used a new approach to calculate the absolute amount of amorphous content using thermal gravimetric analysis (TGA).
Mixtures (0.1, 0.5, 1, 2, 5, 10 and 20 wt.%) of the crystalline and amorphized lactose were made to assess the sensitivity and to obtain the calibration curves with the three different techniques:
•Differential Scanning Calorimetry (DSC) •Microcalorimetry (TAM) •Gravimetric Vapour Sorption (GVS)
Results
Comparison of three methods
Conclusions
• Absolute and accurate amount of amorphous lactose determined (TGA) • Most sensitive method was confirmed to be TAM• Improved GVS method showed to be PSD independent • High troughtput GVS method is versatile for industry applications
Corresponding authors: A.Shevchenko - [email protected] J. Husman-Piirainen - [email protected]
Amorphous content of 5 different commercial lactose grades 1).
In 100% α –LHM, there is 5% of crystall water. In our material, there was 64% of crystalline α –LHM-> the rest 35% is amorphous.
Absolute amount of amorphous content, TGA
3.2% -> amount of crystall water in α
-LHMWei
ght
(%)
Temperature (º)
+ fast - not sensitive
Hea
t fl
ow (
mW
)
Temperature (º)
DSC
+ most sensitive + golden standard
Hea
t fl
ow (
mW
)
Time (hour)
TAM
- PSD sensitive + versatile
Chan
ge in
mas
s (%
)
Time (min)
GVS 1
+ PSD independent + versatile
Chan
ge in
mas
s (%
)
Time (min)
GVS 2
Crystalline = Stable
Amorphous = Unstable
ΔH enthalpy of crystallization
ΔH enthalpy of crystallization
0%
10%
10%
30%
30%
60%
0%
90%
dmdm
¹Δm = dm
¹-dm
²
TAM - 300 480 0,1% + 0,9986
DSC - 10 30 0,5% + 0,9984
GVS 1 + 30 1100,+ 0,1% - 0,9981
GVS 2 + 30 1100,+ 0,1% + n.a.
1) + easy sample preparation not time consuming | - laborous sample preparation2) + multiple sample measurement is possible3) + does not depend on PSD | - depends on PSD of lactose grade
Lactose grade 1 <0,5 0,3 <0,1
Lactose grade 2 <0,5 0,3 <0,1
Lactose grade 3 <0,5 0,6 <0,1
Lactose grade 4 2,2 2,4 3,6 (2,5²)
Lactose grade 5 <0,5 0,3 0,1%
SampleDSC
(%)
TAM
(%)
GVS
(%)
1) Lactose grade 1 to 5 are different PSD grades, from smallest to largest PSD.2) Analysis performed with optimized GVS method
First derivativeWeight loss %