Accelerated stability assessment for an oral N-type calcium channel blocker
Stephanie Buchanan and Sanjay Konagurthu PhD
stephanie.buchanan@thermofisher.com | sanjay.konagurthu@thermofisher.com

Thermo Fisher Scientific

PURPOSEMETHODSRESULTS

Bioavailability Enhancement

Accelerated Stability Assessment Program (ASAP)

Z-160 is an oral N-type calcium channel blocker for chronic
neuropathic and nociceptive pain. The crystalline form
exhibits low solubility and is poorly bioavailable (BCS classII). Physico-chemical properties for Z160 are reportedbelow.

• Tg and water sorption data were used to define
limits in the stressing conditions due to phasetransitions.

The amorphous form of Z160 along with the dispersion
polymer enables fast dissolution and sustained
supersaturation in bio-relevant media, which increases
bioavailability. The lead formulation was selected based on
manufacturability and is a 40:60 Z160:PVP-VA64 spray-driedintermediate (SDI).
The chemical stability of the amorphous form of Z160 is
reduced in comparison to the crystalline form. During theformulation development process, it is important tounderstand the degree of reduction in stability as a result of
the amorphous form. Accelerated Stability Assessment
Program (ASAP) studies were conducted to determine anychanges to product shelf-life predictions in the enabledform.

Formulation
Crystalline Z160
40:60 Z160:PVP-VA64

Lot Number
CMLW-243/13-ZA2
A4-976-71

Spec.
limit (%)
0.5
0.5

ln A

Ea(kcal/mol)B

18.04 ±
6.65
38.11 ±
8.31

16.35 ±
4.57
28.13 ±
5.70

0.027 ±0.01
0.012 ±0.02

R2Q2

0.848 0.689
0.992 0906

• Total degradation was modeled instead ofindividual degradant peaks due different species
growing in for the crystalline sample than in theSDI sample. ASAPprime® was used to modeltime to the specification limit, i.e., isoconversion
time.

• The moisture sensitivity parameter, B, is higher in thecrystalline API than for the SDI indicating degradant
growth in the crystalline API could be more easily
controlled via packaging than in the SDI.
• Probability of passing the specification were higher for
the SDI at 25°𝐶/60%𝑅𝐻 and 30°𝐶/65%𝑅𝐻 in open
packaging, but lower for the SDI at 40°𝐶/75%𝑅𝐻 open.
This result indicates favorable conditions in the SDI at40°𝐶/75%𝑅𝐻 for degradant growth.

Representative ASAP
sample with saturated
salt solution in vial with
Gore-Tex lid, and sample
with perforated foil
covering.

Chemical Analysis• Samples were analyzed for related substances byHPLC.
• Degradants above 0.04% were reported andsummed for the total% degradant in the sample.

Plots of calculated %degradation vs time for (a) crystalline Z160 and (b)40:60 Z160:PVP-VA64 SDI open packaging configurations. Blue curve isthe mean, green and red curves and plus and minus two standard
deviations.

• Lower R2 and Q2 values observed for the crystalline Z160
API, hypothesized to be due to low degradant growth inthe API. The low conversion module in the ASAPprime®
software was utilized for this sample which provides
more conservative predictions.

CONCLUSIONS• The predicted shelf-life for the SDI in open packaging
configurations is longer than for the neat crystalline API.

Condition Selection.

• Packaging the bulk material with desiccant increases theprobability of passing the specification, and specificpackaging configurations will be assessed for the final
dosage form.

OBJECTIVE
Quick Stability Assessment• An ASAP study enabled us to quickly predict productshelf-life for a range of packaging configurations. A typicallong-term stability can take up to 12 months, while an
ASAP study can be completed within 21 to 28 days.

Long-term stability data for Z160 formulation often
displayed complex degradation kinetics and historicalaccelerated stability predictions were typically very
conservative. This is hypothesized to be due to the different
microenvironments present in the SDI sample.
The moisture-modified Arrhenius model built intoASAPprime® only models the initial rate to the specification
limit and provides more accurate predictions.

• Calculated activation energy, Ea, for the isoconversion ofcrystalline Z160 is lower than the 40:60 Z160:PVP-VA64
SDI indicating the energetic barrier to isoconversion ishigher for the SDI.

ASAP study design summary for (a) crystalline Z160 and(b) 40:60 Z160:PVP-VA64 SDI

Probabilities of passing the specification limit of 0.5% total degradation
after 2 years for the crystalline Z160 API and 40:60 Z160:PVP-VA64 SDI.