apd125 tablet formulation screening selection optimization - 14-15 april 2015

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Nelotanserin (APD125) Tablet Formulation Screening, Selection & Optimization

07 December, 2015

Nelotanserin (APD125)

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• A potent & selective inverse agonist for5-HT2A receptors previously investigated as aTreatment for insomnia and related sleep disorders.

• BCS class 2 drug exhibiting good permeability, but extremely low aqueous solubility (< 0.007 mg/mL)

• Exhibits polymorphism (2 anhydrous forms, denoted as Forms I & II, plus an acetonitrile solvate)

• Early clinical trials conducted using soft-gel capsules, containing APD125 solubilized in a lipid matrix– Formulation yielded excellent bioavailability, but exhibited greater degradation

than desired to form 2,4-difluoroaniline (DFA) after one month at 25°C/60%RH and 40°C/75%RH, respectively.

Objective

• Develop a tablet demonstrating superior chemical stability and similar pharmacokinetic exposure to the current soft gel capsule.

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Challenges Unique to APD125

• APD125 is a BCS class 2 drug exhibiting good permeability, but extremely low aqueous solubility (< 0.007 mg/mL)

• APD125 exhibits polymorphism (2 anhydrous forms, denoted as Forms I & II, plus an acetonitrile solvate)

• Acceptable monkey PK results were not achievable using the thermodynamically stable Form II, necessitating the development of the metastable Form I

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• Use of the metastable Form I, exhibiting 3 to 4 times the solubility of the thermodynamically stable Form II

• Micronization of API to increase surface area, reduce particle size, and thereby, maximize dissolution rate

• Addition of a surfactant, SLS, to improve API wettability• Aid dispersion of APD125 particles in water by coating API on PVP

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Steps Taken to Enhance Solubility

Monkey PK Results— Polymorphic Form & Micronization

• Data below shows, in general, Form I performs better than Form II. In addition, methyl cellulose (MC) & povidone (PVP) addition, as well as API micronization enhance exposure in monkeys.

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Impact of SLS upon Aqueous Solubility of APD125

• Addition of SLS significantly improves the solubility of APD125 in water

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Vehicle Solubility (mg/mL)H2O <0.01

0.25% SLS <0.01

0.50% SLS 0.04

0.75% SLS 0.06

1.0% SLS 0.12

Optimal API/PVP Ratio— How much PVP is needed?

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• Assumptions– Used Dv50 from LALLS data as representative particle diameters

for PVP and micronized Form I– Assumed spherical particle shape for both PVP and Form I– Modeled Form I packing on a particle of PVP in both square and

hexagonal arrangements– Assumed the true density of Form I to be the same as the

acetonitrile solvate• Results

– Square packing model – 1:3.8– Hexagonal packing model – 1:3.3

Estimation of Minimum Form I:PVP Ratio required for 100% Loading of Form I on Surface of PVP

Theoretical Minimum Ratio = 1:4

Optimal API/PVP Ratio— SEM Confirmation

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Micronized Form I PVP

1:1 API:PVP 1:3 API:PVP 1:5 API:PVP 1:8 API:PVP

All images @ 500x, except for micronized Form I (3000x)

Visually Determined Minimum Ratio = 1:5

3D Images

Monkey PK Results—Optimal API/PVP Ratio in Tablets

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Formulation Dose (mg) N Cmax(µg/mL) AUCinf (hr•µg/mL) Tmax

(hr)Mean SD Mean SD Mean SD

APD125 FI:PVP 1:1 dry 10 6 0.077 0.057 0.548 0.321 4.7 2.1 APD125 FI:PVP 1:4 dry 10 6 0.085 0.071 0.575 0.379 4.7 4.3 APD125 FI:PVP 1:6 dry 10 6 0.125 0.174 0.572 0.556 4.3 2.3 APD125 FI:PVP 1:8 dry 10 3 0.335 0.138 1.262 0.660 2.7 0.8 APD125 FI:PVP 1:8 wet 10 6 0.227 0.153 1.507 1.218 2.2 1.0 SGC 10 6 0.942 0.303 3.192 1.291 2.2 1.0

1:8 API/PVP appears to provide best exposure in monkeys

Tablet vs SGC—How do they compare?

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Test Article Dose (mg) Cmax (ug/mL) AUCinf (hr.ug/mL)

Softgel #1 40 1.007 5.804

Softgel #2 40 0.971 6.283

Softgel #3 40 1.270 6.054

Softgel 10 0.942 3.192

Wet Granulation Tablet (1:8) 30 0.504 4.988

Wet Granulation Tablet (1:8) 10 0.227 1.507

Direct Compression Tablet (1:8) 10 0.335 1.262

Although tablet shows ca. ½ exposure of SGCs at a 10 mg dose, it appears to become more similar to the SGC at a 30 mg dose.

Steps Taken to Control Solid-State Form

• Good News—Conversion of the metastable Form I to the thermodynamically stable Form II is solvent mediated, meaning if Form I is kept away from direct solvent contact, it appears to remain Form I indefinitely

• More Good News—Methyl cellulose was found to inhibit the conversion of Form I to II in the presence of water

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Effect of Compression/Milling Upon Form I

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Good News—Mortar & pestle milling of micronized APD125 Form I for 1, 5 & 10 minutes didn’t result in a conversion to Form II

More Good News—Compression of micronized APD125 Form I at 2, 5 & 10K PSI didn’t result in a conversion to Form II

Effect of Methyl Cellulose Concentration

• Sample preparation:– Form I/PVP (1:8) direct compression tablets were prepared at 0, 2, 5 & 8% w/w

MC loading. In addition, Form I/coPVP (1:8), direct compression tablets were prepared at a 5% w/w MC loading.

– PXRD was obtained for 1 tablet of each blend to confirm initial presence of Form I.

– Remaining tablets were ground into a composite, weighed, and spiked with an equivalent mass of water to obtain an approximate 50:50 tablet blend/water paste. Samples were stored in 40°C chamber.

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All tablets initially contain Form I


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Tablet without methyl cellulose shows conversion to Form II in less than 24 hrs


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Tablet with 2% w/w methyl cellulose shows conversion to Form II @ 1 wk


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Most samples showing partial or complete conversion to Form II @ 1 month


• Overall, 5% w/w MC or higher yielded best solid-state form stabilization. However, it also resulted in 2 to 3 times the DFA formation rate of 2% w/w MC or lower. Therefore, 2% w/w MC was chosen as the best compromise between best Form I stabilization and minimization of DFA formation.

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Formulation Primary Form

(1 day)

Primary Form

( 1 week)

Primary Form

(1 month)APD 125 FI / PVP (1:8) No methyl cellulose

Form II n/a n/a

APD 125 FI / PVP (1:8) 2% methyl cellulose

Form I Form II n/a


Form I Form I Form I

APD 125 FI / CoPVP (1:8) 5% methyl cellulose

Form I Form I Form II


Form I Form I Form I/II Mixture

Prototype Tablet Accelerated Stability Testing

• “Wet granulation” tablet 3 month stability PXRD results @ 40°C/75%RH show the tablets to still contain Form I

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Form

1

Form

1 Form

1

Prototype Tablet Accelerated Stability Testing

• “Wet granulation” tablet 3 month stability DFA results show a significant improvement over the current SGC, reducing DFA levels by an overall factor of 8:1

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TAM Excipient Compatibility Screening

• Most stable formulations by TAM, defined as exhibiting zero heat transfer as a function of time, were found to be PVP based. In addition, the use of MC was not found to adversely affect chemical stability.

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Steps Taken to Improve Chemical Stability, while Maintaining Exposure

• Utilize tablet rather than liquid formulation, since APIs can be expected to exhibit superior chemical stability in the solid-state, relative to dissolved state

• Dry granulate to minimize potential of both chemical degradation and polymorphic form change

• Micronize the API to maximize surface area• Utilize PVP as a dispersing agent and solubility enhancer• Add a surfactant to improve wettability• Utilize metastable APD125 Form I to improve API dissolution• Add methyl cellulose to inhibit Form I to II conversion upon contact

with water• Protect final tablets from moisture uptake via application of a

OPADRY II PVA BLUE coating

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Conclusions

• Through the collaborative efforts of Arena scientists in multiple groups/departments, APD125 prototype tablets have been successfully developed, with preliminary data indicating good PK exposure in monkeys, superior chemical stability and effective solid-state form control.

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40 mg tablets

Acknowledgements

• Justin Bach• William Betts• Deam Given• Natalie Jamgochian• Nada Mitic• Mike Morgan• Maiko Nagura• Yun Shan• Jesse Shao

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Divider Page

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Abstract

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Tablets provide a number of key advantages over liquid formulations—better chemical stability, lower manufacturing cost & typically higher manufacturing volume & speed. In the case of APD125, a tablet formulation offers the potential of a significant improvement in chemical stability over the soft gel capsule. However, a number of important challenges exist, with respect to bioavailability and polymorphic form stabilization. In the case of bioavailability, proper polymorphic form selection and particle size control was found to be essential, along with the novel use of PVP and methyl cellulose to enhance solubility and solid-state form stabilization, respectively. This presentation details the research efforts supporting the successful development of the APD125 prototype tablets.

Nelotanserin (APD125) Tablet Formulation Screening, Selection & OptimizationAlani Selvey , Justin Bach, Deam Given, Jesse Shao, Maiko Nagura, Mike Morgan, Nada Mitic, Natalie Jamgochian, William Betts, Yun Shan

apd125 tablet formulation screening selection optimization - 14-15 april 2015

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