Solid-State Chemistry: The Next Focal Point for Drug Design and Development

Weili Yu Pharmaceutical Sciences Pfizer, Groton, CT 06340

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Why worry about API solid form?

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Pfizer Confidential │ 3

API Solid Form

Bioavailability

Manufacturabilty Stability

•  Solubility •  Dissolution rate •  Precipitation

•  Phase purity •  Excipient compatibility •  Hygroscopicity

•  Particle morphology •  Sticking tendency •  Compressibility

Why worry about API solid form?

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Physical and Chemical Stability

Salt disproportionation and degradation

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HN

Cl

Cl

q  Sertraline §  Serotonin reuptake inhibitor §  pKa: 9.1 §  Intrinsic solubility: 4 µg/ml

q  Micronazole § Antifungal §  pKa: 6.9 §  Intrinsic solubility: 1 µg/ml

Material

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q  To investigate the impact of counter ion on the potential of salt disproportionation

q  To explore the relationship between salt disproportionation and chemical stability (oxidation)

Objectives

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Solu

bilit

y

pH

spa K

SpKpH 0max log+=

pHmax

Solid phase: free base

Solid phase: salt

Region I

Region II

pHmax

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q  In a powder system, above pHmax, salt of a free base is driven by thermodynamics to disproportionate and convert to the free form.

q  Acidic conditions have a protective effect for an amine functional group against oxidation. In a powder system, salts of free base should be less susceptible to oxidation.

Hypotheses

Salt Free Base

Oxidation products

Disproportionation Oxidation

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Experiments q  Salt screen was conducted with both Sertraline and

Miconazole.

q  Salt disproportionation was induced by mixing the salts with tribasic sodium phosphate dodecahydrate (TSPd) and the mixtures were placed at 57% RH at 25C.

q  The extent of salt disproportionation was monitored by Raman spectroscopy over time.

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3000 2000 1000 0

Sertraline

Sertraline mesylate

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Mole ratio (FB/salt)

Peak

inte

nsity

(278

5 / 3

010)

Y = 0.5423x + 0.0398 R = 0.9981

Quantification by Raman

Raman Shifts (cm-1)

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Unique Raman shifts

Material Raman shift Calibration R2 Miconazole 1506 -

Miconazole camsylate 1743 0.9994 Miconazole mesylate 780 0.9973

Miconazole nitrate 1328 0.9880 Miconazole phosphate

monohydrate 896

0.9933

Miconazole tosylate 1124 0.9992 Sertraline 783†, 2785 -

Sertraline benzoate 1385 0.9938 Sertraline HCl 1405 0.9824

Sertraline hemitartrate 2875 0.9956 Sertraline mesylate 3010 0.9981

†783cm-1 was used as unique Raman shift for sertraline free base in comparison to sertraline HCl due to interference at 2785cm-1

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Salt disproportionation over time

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Relationship between pHmax and extent of disproportionation

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pHmax and salt solubility

Salts Calculated pHmax

Solubility (M)

Miconazole camsylate 4.17 1.27×10-3

Miconazole mesylate 1.44 6.88×10-1

Miconazole nitrate 4.75 3.36×10-4

Miconazole phosphate monohydrate 3.35 8.53×10-3

Miconazole tosylate 4.44 6.97×10-4

Sertraline benzoate 7.11 1.17×10-3

Sertraline HCl 6.04 1.38×10-2

Sertraline hemitartrate 6.65 3.35×10-3

Sertraline mesylate 5.68 3.11×10-2

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HN

Cl

Cl

Cl

Cl

O

Cl

Cl

N

OH

N

O

H3C

Cl

Cl

Cl

Cl

OH

HN

Sertraline oxidative degradation

Tetralone

4-Hydroxy-Sertraline

LP3

Oxime

Sertraline

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Sertraline solution sample stability

Sertraline solution samples

% Sertraline remaining after 14 days

Sertraline solution + 3% H2O2

(pH 9.5) 88.24%± 0.34%

Sertraline solution + 3% H2O2

(pH 2.0)

100%

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Sertraline powder sample stability

% Sertraline Remaining

Sertraline Sertraline Benzoate

Sertraline HCl

Sertraline Hemitartrate

Sertraline Mesylate

4 days 99.53 ± 0.01 100 100 100 100

9 days 97.57 ± 0.10 100 100 100 100

14 days 95.45 ± 0.35 100 100 100 100

§  Sertraline free base / salt (10%) + solid state H2O2 (90%) §  25C / 57%RH

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Sertraline powder sample stability

§  Sertraline free base / salt + solid state H2O2 + TSPd (1:1:1 in wt) §  25C / 57% RH

After 9 days Free Base Sertraline Benzoate

Sertraline HCl

Sertraline Hemitartrate

Sertraline Mesylate

% Disproportio-

nated N/A None

Detected ~10%

~5%

~23%

% Sertraline remaining

97.11 ± 0.09

99.23 ± 0.04

96.53 ± 0.04 93.62 ± 0.09 96.05 ±

0.14

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Conclusions

Ø  Extent of salt disproportionation was found to be highly dependent on the pHmax values.

Ø  Salts with higher solubility (thus lower pHmax) have a greater tendency to disproportionate and convert to free base in presence of basic excipients.

Ø  Sertraline salts are much more prone to oxidation upon disproportionation and conversion to the free base. The protective effect of protonation on amine function group was demonstrated in both solution and powder systems.

Yi-Ling Hsieh, Weili Yu, Yanqiao Xiang et al., International Journal of Pharmaceutics, 461, 2014

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Bioavailability

Solubility = Bioavailability ?

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MoreSolubleForm

LessSolubleForm

AbsorbedDrug

DissolvedDrug

DissolvedDrug

Disso Fast

Precipitation

Disso Slow

Absorption

Absorption

Possible mechanisms

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Cocrystal (Compound 2) - Increased aqueous dissolution rate by 18-fold - AUC increase at least 3-fold (5 & 50mg

doses)

D. McNamara, S. Childs et al, Pharmaceutical Research, V23, No.8, 2006

•  pKa = -0.7 •  Aqueous solubility

<0.1ug/mL

Compound 2 : Glutaric acid cocrystal Compound 1 : API (Sodium channel blocker)

Example 1: Glutaric acid cocrystal

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Example 2: Carbamazepine •  Static disk dissolution @ pH 1.2 (0-10 min) •  Solubility: Form III > Form I > Dihydrate (pH 1.2)

Y.Kobayashi, S. Ito, S. Itai, K. Yamamoto, Int J Pharm 193 (2000) 137–146

•  Powder dissolution @ pH 1.2 •  Form III converted to dihydrate more rapidly

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§  At 40mg dose, similar AUC §  At 200mg dose, AUC Form I > Form III > Dihydrate §  Rapid conversion of Form III to the dihydrate led to lower bioavailability

Y.Kobayashi, S. Ito, S. Itai, K. Yamamoto, Int J Pharm 193 (2000) 137–146

Example 2: Carbamazepine

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Example 3: Fluoxetine HCl co-crystal

S.L. Childs, L. J. Chyall and J. T. Dunlap et al., JACS, 2004, 126, 13335-13342

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Remarks q  Meta-stable forms do not necessarily result from meta-stable polymorphs. Far more common, they occur when a ambient-stable form is put into the GI track (e.g. salt of a free base is dosed).

q  Conversion to a more stable form, will, in general, occur more rapidly as the energy difference between the two forms increases.

q  Therefore, in many cases, the common practice of selecting more soluble form may not provide the highest level of drug in solution in the GI track.

q  Small scale experiments can be performed to evaluate the potential for form conversion on the time scale of absorption.

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Manufacturability

The role of API particle size

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q  Impact on bioavailability

Smaller particle size => faster dissolution rate => increased bioavailability => Product Efficacy

q  Impact on dosage form content uniformity

Smaller particles

Better dosage form content uniformity Improved product safety and efficacy

Example 1mgA dosage forms

Common roles played by particle size

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q  Impact on Stability

Smaller particle size Larger surface area increased contact area with excipients more significant degradation

q  Impact on drug product manufacturability

§  Powder flow – need to have the right flow for the right dosage form

§  Segregation potential – larger differences in particle size leads to higher segregation potential

§  Bulk density - capsule filling, tablet press die filling

§  Mechanical properties – non-linear dependence on particle size

§  Dissolution rate – critical for liquid dosage form manufacturing

Common roles played by particle size

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ICH Guidance

Content  Uniformity  

Stability  

Processability  Dissolu6on,  solubility  or  bioavailability  

Par6cle  size  Specifica6on  

API particle size specification is required for all solid dosage forms or liquid containing undissolved API if particle size is critical to any of the following properties:

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What’s available for CU prediction?

Intellipharm

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In-house Model (SimCU) Features SimCU

Can use experimental PSD YES

Consider API PSD variability YES

Consider Mean Tablet Weight YES

Consider Tablet Weight Variability YES

Usage of current USP guideline to estimate probability of failure YES

Batch processing capability YES

Applicable to Drug Product Intermediate YES

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q  Tested on at least 5 different drug products and 20 DP lots q  API doses ranging from 0.5mg to 250mg

q  API loading from 0.5% to 50%

q  Tablets and capsules

q  Broad API particle size range

§  D[4, 3]: 8µm – 198µm §  D[v, 90]: 15µm – 334µm

How well does the model work?

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Remarks q  Accurate prediction of dosage form content uniformity allows creation of meaningful particle size acceptance criteria at early stage of development.

q  Prediction of the model can be revised and optimized as data from large-scale manufacturing becomes available to guide late stage development decisions (API milling, de-lumping of agglomerates etc.).

q  Provide a strong theoretical support for regulatory filing of final particle size specifications.

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q  API solid form and the associated physical attributes plays a key role in drug design from discovery to commercialization.

q  Identification and selection of appropriate API solid form at the earliest possible stage could be advantageous. The dividing line between discovery and development is getting blurry.

q  Practical challenges may include §  Limited material §  Balance between front loading work and attrition §  Development strategy of multiple lead compounds

q  Leverage computational tools and small-scale experiments with clinical and large scale manufacturing experience.

Summary

Acknowledgement

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Yi-Ling Hsieh Sal Garcia Yanqiao Xiang Weitao Pan Ken Waterman Sheri Shamblin Evgenyi Y. Shalaev Lynne Taylor