determination of the absolute amount of low amorphous ...100,+ determination of the absolute amount...

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100,+ Determination of the absolute amount of low amorphous content in commercial inhalation lactose grades: TAM, DSC and GVS compared S. 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 -LHM Weight (%) Temperature (º) + fast - not sensitive Heat flow (mW) Temperature (º) DSC + most sensitive + golden standard Heat flow (mW) Time (hour) TAM - PSD sensitive + versatile Change in mass (%) Time (min) GVS 1 + PSD independent + versatile Change in mass (%) Time (min) GVS 2 Crystalline = Stable Amorphous = Unstable ΔH enthalpy of crystallization ΔH enthalpy of crystallization 0% 10% 10% 30% 30% 60% 0% 90% dm dm ¹ Δm = 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 preparation 2) + multiple sample measurement is possible 3) + 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% Sample DSC (%) 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 derivative Weight loss %

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Page 1: Determination of the absolute amount of low amorphous ...100,+ Determination of the absolute amount of low amorphous content in commercial inhalation lactose grades: TAM, DSC and GVS

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 %