Water in Food, Lausanne 2004

Transcription

1 Water in Food, Lausanne 2004 Characterising the Amorphous State in a Pharmaceutical Powder Using Moisture and Organic Vapour Sorption Frank Thielmann,* Daniel Burnett,** Jürgen Adolphs,*** *Surface Measurement Systems London, UK **Surface Measurement Systems, Allentown (PA), USA ***POROTEC GmbH, Hofheim/Ts Ts., Germany

2 Overview I. Introduction into the Technique II. III. Applications a) Glass Transition Determination b) Video Microscope Observations c) Amorphous Content Quantification Summary

3 Amorphous Materials No long-range or well-defined molecular structure - only short range molecular order Often introduced via spray-drying, freeze-drying, milling, or processing Desired qualities Higher solubility, higher dissolution, or better compression characteristics Undesired qualities Decreased chemical and physical stability Thermodynamically metastable compared to crystalline state

4 Amorphous Materials and Water Water vapour present during processing and storage Hydrophilic amorphous solids often absorb higher amounts of water vapour compared to crystalline phase Sorbed water can act as plasticizing agent, lowering effective T g Lowering glass transition temperature Spontaneous phase transition and/or lyophile collapse Critical threshold RH at processing, storage, or delivery conditions to prevent spontaneous glass transition

5 Dynamic Vapour Sorption Experiment time reduced to hours instead of days Small sample size reduces time needed to establish equilibrium Continuous monitoring of mass as a function of relative humidity (0 to 98% RH) Full control and monitoring of sample environment Fast sorption/desorption kinetics may be studied Gravimetric automated flowing gas system Range of temperatures Full use of water and organic vapours

6 Dynamic Flow Instrumentation Temperature Controlled Chamber Microbalance Module Humidity Regulated Dry Gas Flow Control Module Vapor Generator Module Sample Module Sample Reference CCD Camera

7 Material Morphology and Vapour Sorption Amorphous- Glassy Solid T <T g Mainly surface adsorption Fast kinetics and low uptake levels Amorphous- Rubbery Solid T >T g Deep bulk sorption Slow kinetics and large uptake levels Crystalline No T g Surface adsorption Fast kinetics and very low uptake

8 Glass Transition RH (T g RH) Linearly ramp from 0 to 90% RH for a spray-dried lactose powder Shift in vapour sorption mechanism at glass transition Surface adsorption versus bulk absorption as molecules begin to move into bulk Higher free volume in amorphous phase Higher surface area and/or energy for amorphous state Perform experiments over a range of ramping rates Extrapolate to an infinitely long ramping rate or 0% RH/hour Determine threshold RH at a specific T to prevent glass transition at particular temperature Tg RH

9 DVS Glass Transition Date: 05 Dec 2002 Time: 11:58 am File: lactoseramp900.XLS Sample: amorphous lactose Change In Mass (%) - Dry Surface Adsorption Glass Transition DVS Change In Mass (dry) Plot % Change in Mass Target RH Recrystallization Bulk Absorption and Surface Adsorption Temp: 25.1 C Meth: lactoseramp min.sao M(0): Target RH (%) 0 0 DVS - The Sorption Solution Time/mins Surface Measurement Systems Ltd UK

10 0 to 90% RH for Different Ramping Rates Amorphous Lactose Temp: 25.0 C % RH/hour 4% RH/hour Net Change In Mass % RH/hour 8% RH/hour 10 % RH/hour DVS - The Sorption Solution Time/mins Surface Measurement Systems Ltd UK

11 Humidity at Glass Transition (%RH) T g RH versus Ramping Rate Glass Transition Humidity (Tg RH) versus Humidity Ramping Rate y = 1.155x R2 = Ramping Rate (%RH/hour) Critical T g RH = 30% +/- 1% RH at 25 C

12 Collapse RH versus Ramping Rate Humidity at Recrystallization (%RH) y = 1.252x R 2 = Ramping Rate (%RH / hour) Critical Collapse RH = 58% RH at 25 C

13 Video Results (25 C, 6% RH/hour) Amorphous Lactose Net Change In Mass (%) C B D A Time/mins

14 Comparisons with DSC Data T g = ~35 C at 0.30 water activity (30% RH) Similar to T g RH measured with DVS Active RH control in DVS experiments Source: Y. H. Roos, Department of Food Science, Food Technology, and Nutrition; University College Cork, Ireland

15 Comparisons with Microcalorimetry Data Moisture-induced thermal activity trace with 3% RH/hour ramp Similar structure to DVS results ~30% RH-internal structure change, critical storage RH ~58 % RH-re-crystallization D. Lechuga-Ballesteros, A. Bakri, and D.P. Miller, Pharmaceutical Research, Vol. 20 (2), 308 (2003).

16 IGC T g Measurement 14 Tg 12 ln(vn/t) Crystallisation Surface ads. + bulk absorption Crystalline + amorphous surface ads /T (1/K) Similar results for any second order phase transition

17 Comparisons with IGC data Glass Transition Temperature of Amorphous Lactose versus Relative Humidity Glass Transition Temperature, Tg (K) Relative Humiidty (% RH) Tg (K) Power (Tg (K)) Values between 25% RH (27.1 C) and 30% RH (22.2 C) compare well with DVS data at 25 C (30 %RH)

18 Amorphous Content Analysis Quantification of residual amorphous content of pharmaceutical materials is a crucial and commonly difficult analysis. A number of issues need to be considered for choice of an appropriate methodology.

19 Choosing a Technique for Amorphous Content Determination Factors to consider: Online or off-line analysis Quality or resolution of analysis required Amount of sample to be characterized Time available for analysis Knowledge base within lab or group Destructive or Non-destructive Sample preparation requirements

20 My Ideal Choice? Could be used online or off-line Resolution of 0.01% Sample size - 1mg Analysis time - 5 minutes Equipment- Easy to use Approach- Non-destructive Minimal sample preparation or method development

21 Amorphous Content Analysis Techniques in usage including detection limit and analysis time: Differential Scanning Calorimetry (DSC) 10% (<1 hour) Powder X-ray Diffraction (PXRD) 5% (<1 hour) Thermal Stimulated Current Spectroscopy 2% (<1hour) Density 10% (<1 hour) Solution Calorimetry 1% (< 10 minutes) FT-Raman 1% (<1 hour) Near IR 1% (<1 hour) Modulated DSC 1% (< 2 hours)

22 Amorphous Content Analysis The most sensitive techniques in usage include: Solid State NMR 0.5% (<1/2 day) Difference in NMR spectra of crystalline and amorphous phases Microflow Calorimetry 0.4% (<1/2 day) Heat of crystallization of amorphous phase Parallel Beam XRPD 0.4% (<1 hour) Difference in diffraction behaviour of crystalline and amorphous phases Gravimetric Vapour Sorption 0.2% (<1 day) Mass uptake due to preferential solute uptake by amorphous phase including inducing amorphous to crystalline transformation.

23 Gravimetric Characterization Change In Mass (%)-Dry Relative pressure RH D Amorphous Content Time/mins DVS change in mass profiles for a sample of X with a 4.8% amorphous content L. Mackin et al, Int. J. Pharm.,

24 DVS Amorphous Content Octane adsorption of mixtures of amorphous lactose and a-lactose monohydrate DVS Isotherm Plot Temp: 25.0 C Change In Mass (%) - Dry % Crystalline 2.170% Amorphous 6.017% Amorphous % Amorphous 100% Amorphous Target p/po (%) Surface Measurement Systems Ltd UK DVS - The Sorption Solution

25 Octane Uptake versus Amorphous Content Octane uptake at 0.95 p/po (% change in mass) Calibration curve for lactose at 0.95 p/po y = 1.797E-03x E-02 R 2 = Commercially available a-lactose monohydrate from Acros Amorphous content: 0.9 % (+/- 0.3%) % Amorphous Content

26 Future Studies Perform additional experiments over range of temperatures Study other amorphous systems (i.e. excipients, API s, complete formulations) Closer look at DSC, microcalorimetry, and modelling results to elucidate nature of discrepancies and confirm assignment of features in DVS data

27 Conclusions New technique for simply measuring the critical RH for a glass transition event Study kinetics of water-induced morphologic changes Determine the threshold storage conditions to prevent glass transition and recrystallization Determination of amorphous content without the need to recrystallize amorphous phase

28 Water in Food, Lausanne