Physical Stability of Amorphous Solid Dispersions: Computational

Studies of ‘Miscibility’I. Ivanisevic, S. Bates, P. ChenSSCI, a division of Aptuit IncL. Taylor and A. Rumondor

Purdue University

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Outline• Amorphous state and its stability and

performance• ‘Miscibility’ characterization tools• XRPD and computational methods:

• Linear combinations of XRPD patterns• Linear combinations of PDF patterns• Pure Curve Resolution Method

• Examples throughout!• Physical stability study• Effects of humidity and temperature on

dispersion miscibility

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Amorphous State: Solubility and Dissolution Rate

• Higher aqueous solubility (maximum value, Cmax) and initial dissolution rate at any given temperature1,2: 1.5-10x increase over crystalline forms typical

Experimental aqueous solubility profiles for amorphous and crystalline indomethacin

[1] Hancock, B.C. and M. Parks, Pharm. Res., 2000. 17(4): p. 397.[2] Grant, D.J.W. and T. Higuchi, Solubility behavior of organic compounds,1990

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Amorphous State: Physical Stability

• Thermodynamically unstable, will crystallize• Rate of crystallization affected by temperature,

humidity, presence of water and other factors

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Amorphous Dispersions

• Systems combining API and excipient(s)• Expected to provide enhanced dissolution rates

and increased maximum solubility (vs. crystalline forms) and greater physical stability (vs. amorphous state)

• In practice? – Initial dissolution rates and Cmax typically significantly

higher than crystalline forms– Physical stability often appears to depend on drug-to-

excipient ratio, storage conditions etc.

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Example: Ritonavir• Ritonavir is a large, lipophilic molecule that is very poorly

soluble in aqueous media and exhibits an extremely slow intrinsic dissolution rate

• Oral absorption of ritonavir appears to be limited by both dissolution and permeability, making it a BCS Class IV compound

• Study3 evaluated solid dispersions of polyethylene glycol (PEG) and amorphous ritonavir at different drug loadings

• Both in vitro (0.1N HCl with a USP Apparatus I) and in vivo (beagle dogs) performance were evaluated

[3] Law, D. et al, J. Pharm. Sci., 2004, 93(3): p. 563-570

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Ritonavir Dispersions:In Vitro Dissolution Performance

a) Physical mixture of crystalline ritonavir and PEG (10:90) (w/w)

b) Amorphous dispersion 10:90 (w/w)

c) Amorphous dispersion 20:80 (w/w)

d) Amorphous dispersion 30:70 (w/w)

Data by Law et al. [3]

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Ritonavir Dispersions:In Vivo Bioavailability Performance

a) Crystalline ritonavirb) Amorphous dispersion 10:90 (w/w)c) Amorphous dispersion 20:80 (w/w)d) Amorphous dispersion 30:70 (w/w)

All dispersions with PEG.Data collected on fasted dogs by Law

et al. [3]

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Predicting Amorphous Dispersion Performance

• Historically hard to do without lengthy and costly stability/bioavailability studies

• Prediction?• Characterization tools:

• mDSC• XRPD• Spectroscopy (IR, Raman, NMR)• High-resolution microscopy• Melting point depression

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Miscibility

phase separated mixture

solid nanosuspension

polymer API

amorphous miscible dispersion

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Miscibility Analysis: Thermal Methods

• Measure glass transition temperature (Tg)• 2 Tg = physical mixture, 1 Tg = molecular

dispersion• Industry standard but…

– Resolution limitations: • physical mixtures with amorphous domain sizes <

~30 nm may exhibit single Tg4

– Changes in temperature may change the miscibility of the system

[4] Newman et al., J. Pharm. Sci., 97(11), 2008, pp. 4840-4856.

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Example: Dextran-PVP K90• Prepared by freeze drying (lyophilization) from aqueous solution• mDSC results indicate phase separation

PVP

Dextran

70% PVP

30% PVP

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Pimozide-PVP: DSC data

Pimozide

Dispersion ofPimozide (40%)and PVP (60%)

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A Note on Sample Preparation…

• Properties of amorphous materials can be greatly affected by method of preparation

• For these studies (unless otherwise noted):

The dispersion samples were produced by dissolving in a common solvent (e.g. ethanol-dichloromethane mixture). The solvent was then removed by rotary evaporation, and the sample stored under vacuum for 2-12 hours.

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Computational Techniques1. Linear combinations: Measured XRPD patterns

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Computational Techniques2. Linear combinations: Pair Distribution Functions

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Linear Combinations

• Model each dispersion as a linear combination of the API and excipient using XRPD or PDF patterns

• If system is phase separated: – model should agree with measured patterns – ratio of components in model should be

similar to component weight ratio in dispersion

• Otherwise system is ‘miscible’

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Dextran-PVP: XRPD Patterns

Dextran

PVP

Blue – Measured XRPD pattern of 40:60 Dextran-PVP dispersionRed – Calculated XRPD pattern at 35:65 Dextran-PVP

Good fit, phase-separated dispersion!

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Example: Pimozide-PVP K29/32

• Six dispersions (2:8, 3:7, 4:6, 6:4, 7:3, 8:2 Pimozide:PVP) prepared and analyzed by DSC, IR, XRPD and computational methods

• mDSC detected a single Tg, value varied by composition (miscible system)

• IR data also indicated miscibility (specific interactions between Pimozide and PVP)

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Pimozide-PVP: XRPD Patterns

PimozidePVP

Blue – Measured XRPD pattern of 40:60 Pimozide-PVP dispersionRed – Calculated XRPD pattern at 37:63 Pimozide-PVP

Poor fit, ‘miscible’ dispersion!

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Example: Felodipine-PVP K29/32 and Felodipine-PAA

• IR spectroscopy data for FEL-PVP detect formation of H-bonds between FEL-PVP

• Therefore, system is thought to be miscible• Miscibility for FEL-PVP persists over a wide

range of drug loadings• A single Tg is detected for FEL-PVP dispersions• IR spectroscopy data for FEL-Polyacrylic acid

(PAA) reveals no change in H-bonding• Two Tg are detected for FEL-PAA dispersions

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PVP aloneCrystalline Felodipine (no PVP)Amorphous Felodipine (no PVP)

Felodipine-PVP Hydrogen Bonding Interactions

Felodipine-PVPdispersions (bottom-to-top increasing PVP content)

IR data

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Felodipine-PVP: PDF Data

FelodipinePVP K29/32

Blue – PDF pattern of 70:30 Felodipine-PVP dispersionRed – Calculated PDF pattern at 63:37 Felodipine-PVPGreen – Residual (difference) between the two

Distinct residual, miscibile!

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Felodipine-PAA: PDF Data

Felodipine

PAA

No distinct residual, immiscibile!

Blue – PDF pattern of 70:30 Felodipine-PAA dispersionRed – Calculated PDF pattern at 71:29 Felodipine-PAAGreen – Residual (difference) between the two

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Linear Combinations Notes• Method is sensitive to:

– quality of reference XRPD patterns– experimental artifacts in measured data

• Need reference pattern of amorphous API, sample must be prepared using the same process as the dispersion

• PDF method more robust, can be harder to interpret results

• Qualitative (not quantitative) measure of ‘miscibility’

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XRPD Data QualitySample of amorphous nifedipine:

- analyzed in a glass capillary, normal atmosphere- analyzed in a low-background holder, using He purge

Local structuremuch easier tospot in bottomanalysis!

Bottom pattern issuitable for computationalanalysis, top is not!

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3. Pure Curve Resolution Method (PCRM)

Computational Techniques

XRPD patterns of dispersions of nifedipine and PVP

PVP-NIF (3:7)

PVP-NIF (4:6)

PVP-NIF (6:4)

PVP-NIF (7:3)

Nifedipine

PVP K29/32

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PCRM

• Analyzes the variance in measured dispersion data sets (prepared at different loadings) to extract the pure curves (PCs)

• PCs can then be compared to measured reference patterns of API and excipient

• If good match and no residual components detected, system is phase separated

• Otherwise ‘miscible’[5] Ivanisevic et al. A novel method for the assessment of miscibility in amorphous dispersions, J. Pharm. Sci. in press Mar 2009.

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Example: Nifedipine-PVP K29/32

• IR spectroscopy results indicate nifedipine and PVP form H-bonds (miscibility)

• One Tg observed by DSC for this system• Computational analysis (linear

combinations) suggests miscibility• Four dispersions (30:70, 40:60, 60:40,

70:30 nifedipine:PVP) used as input into the PCRM

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Nifedipine-PVP: PCRM Analysis

Blue – Measured XRPD pattern of amorphous nifedipineRed – First PC calculated from 4 dispersion patterns of nifedipine-PVP

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Nifedipine-PVP: PCRM Analysis

Blue – Measured XRPD pattern of PVP K29/32Red – Second PC calculated from 4 dispersion patterns of nifedipine-PVP

Peak shifting between measured and calculated patterns.

Miscible system.

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Example: Trehalose-Dextran T500

• System previously reported to exhibit single Tg [6]

• Two Tg and trehalose crystallization observed after humidity stress is applied [6]

• Seven dispersions (2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2 Trehalose:Dextran) used as input into the PCRM

[6] M. Vasanthavada et al. Pharm. Res. 21(9): 1598-1606 (2004).

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Trehalose-Dextran: PCRM Analysis

Blue – Measured XRPD pattern of trehaloseRed – First PC calculated from 7 dispersion patterns of trehalose-dextran

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Trehalose-Dextran: PCRM Analysis

Blue – Measured XRPD pattern of dextranRed – Second PC calculated from 7 dispersion patterns of trehalose-dextran

No peak shifting for eithercomponent and no new components.

Phase-separated system!

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Example: Ketoconazole-PVP K29/32

• System previously reported to be both immiscible [7] and miscible [8]

• Four dispersions (3:7, 4:6, 6:4, 7:3 KET:PVP) used as input into the PCRM

• DSC data: 2 Tg at 7:3, 6:4, 1 Tg at 4:6, 3:7• IR data inconclusive (partial miscibility at

low drug loadings?)[7] Van Den Mooter et al., Europ. J. Pharm. Sci. (12) 2001, pp 261.[8] Marsac et al., Pharm. Res., DOI 10.1007/s11095-008-9721-1, 2008.

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Ketoconazole-PVP: PCRM Analysis

Blue – Measured XRPD pattern of amorphous ketoconazoleRed – First PC calculated from 4 dispersion patterns of ketoconazole-PVP

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Ketoconazole-PVP: PCRM Analysis

Blue – Measured XRPD pattern of PVPRed – Second PC calculated from 4 dispersion patterns of ketoconazole-PVP

Peak shifting between measured and calculated patterns.

Miscible system.

But perhaps not at all loadings of ketoconazole:PVP (based on DSC/IR data)!

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Ketoconazole-PVP: PDF Analysis

• PDF analysis of individual dispersion XRPD patterns to detect miscibility

• Good fit indicating mostly phase separated system at 7:3 ketoconazole:PVP

• Fit gets worse with decreased ketoconazole loading (6:4, 4:6, 3:7)

• Conclusion: system is miscible at low loadings of ketoconazole (e.g. 3:7)

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PCRM Notes

• Requires at least two dispersions with different loadings of API and excipient

• Can be used to calculate unknown amorphous reference patterns (e.g. for amorphous API with low Tg)

• Leads into ‘miscibility index’ calculations –potentially quantitative measure of ‘miscibility’

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Physical Stability Study

• Dispersions exposed to ambient conditions (~25°C/50%RH) and monitored for physical stability using XRPD

• 2 different loadings tested, 30/70, 70/30 API-excipient

• Multiple samples tested in some cases• Both phase-separated and miscible

dispersions included in the study

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Physical Stability Results

Amorphous felodipine

Felodipine after 24 hrs at 25°C/50%RH

Dispersion of felodipine 70% and PVP K29/32 30%Felodipine 70% PVP K29/32 30% after 9 months

Ambient conditions, 25°C, 50% RH

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Physical Stability of Miscible Dispersions (Ambient Conditions)

• Felodipine-PVP (30 and 70% API loading): amorphous after 9 months

• Nifedipine-PVP (30 and 70% API loading): 98+% amorphous after 9 months

• Indomethacin-PVP (50 and 60% API loading): amorphous after 10 months

• Ketoconazole-PVP (30% API loading): remained amorphous for 7 months, then started to crystallize (<10% crystalline after 8 months of storage)

• All of these amorphous drugs crystallize within days when not stabilized by excipient.

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Physical Stability of Phase-Separated Dispersions

Phase-separated system proved unstable under ambient conditions (25°C/50%RH) after less than 1 month

Felodipine 40% PAA 60% -initially amorphous

Felodipine 40% PAA 60% after 1 month ambient

Felodipine

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Physical Stability of Phase-Separated Dispersions (2)

Phase-separated system proved unstable under ambient conditions after 4 months

Ketoconazole 70%PVP 30%

Ketoconazole 70% PVP 30% after 4 months

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Conclusions

• We apparently can determine whether a dispersion is phase separated or miscible

• Data quality and use of multiple techniques are important for this work

• Lots of examples of miscible systems – common property?

• Future work (short term): – ‘miscibility index’ – Connection to physical stability and bioavailability

Effects of temperature and relative humidity on dispersion

miscibility

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Premise

• Accelerated aging studies are common methods of evaluating dispersion stability

• 40°C/75% RH stress commonly used• Stability data is often extrapolated to

ambient conditions• Oft-cited rule of thumb: 1 month stability at

40/75 equals 6 months stability at ambient• Does this apply to miscible dispersions?

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Felodipine/PVP

• H-bonding interactions studied by FTIR as a function of temperature and RH

• Also used XRPD, AFM, DSC and SEM• Different dispersion compositions were

studied – H-bonding observed over the full range of compositions (30-74% API)

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Effects of temperature on miscibility

• Increasing temperature weakened the interactions between FEL and PVP, but they persisted up to melting point of drug

• Changes in H-bonding interactions were found to be reversible with changes in temperature

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Effects of humidity on miscibility

• Introduction of water into dispersions at room temperature irreversibly disruptedinteractions between FEL and PVP

• DSC, AFM and SEM confirmed these results

• Moisture-induced immiscibility occurred at or above 75% RH

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FEL-PVP XRPD DataRed pattern: 70% felodipine, 30% PVP (solid dispersion)Black pattern: same composition, after 18 hours under 94% RH stress

Structural changes can be observed in the amorphous phase (halo shift at ~12 °2θ)

Material started to crystallize

Same system remained amorphous for 9+ months at 25 °C and <70% RH

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Acknowledgments

• Simon Bates, Ping Chen, SSCI• Claire Gendron, David Engers, Paul Schields,

Kevin Leach, Erin VanMeter, Ping Chen, Jan-Olav Henck, SSCI

• Prof. Lynne Taylor and Alfred Rumondor, Purdue University