Preformulation & Clustering Analysis

Michael BorutaIndustrial Solutions Manager

Optical Spectroscopy Product Manager

Outline

• Background

• Challenges

• Managing Data

• Clustering

• Review & Decision Making

• Summary

Preformulation Background• Preformulation involves the application of biopharmaceutical

principles to the physicochemical parameters of a drug with the goal of designing an optimum drug delivery system.

• Different Stages of Preformulation– Selection of appropriate salt and polymorph form

– Characterization the solid-state properties of the drug substance

– Determination of solution properties

– Determination of compatibility with excipients

• At the start of preformulation a target has been identified and the patent process has started – therefore the clock starts ticking

PROCESS

DEVELOPMENTDISCOVERY

PRE-

FORMULATIONCLINICAL MFG

PRODUCT

LAUNCH

Interface Between Drug Substance and Drug Product

What Is Salt Selection?

• Simply put—it is creating various salt forms for a target API.

• Creating salts is not an exact science. It uses a trial and error approach with some guidance from past experiences.

• There are many possible combinations of solvent ratios, acids, bases, that could be used to produce salts along with various conditions such as application of heat, anti-solvents, or seed crystals.

• HTS allows many possible combinations to be attempted with low sample requirements

What Are Polymorphs?• Simply put – polymorphs are different crystal forms of the same compound.

– A different packing order in the crystal, means different molecular associations between adjacent molecules.

– These different associations can change energy levels of the atoms and the crystal lattice.

– Changes in the energy levels lead to changes in the properties of the materials; stability, bio-availability, etc.

• It is rare for a compound to have a single crystal form. One of the fears of the pharma people is did I miss a crystal form – this could lead to patent infringement.

• The conditions that are used to create crystals (the salt selection process) can effect the form of the crystal.

• HTS allows many possible combinations to be attempted with low sample requirements

Challenges

• Labs are now running more experiments to find possible salt forms and polymorphs

• Laboratory instrumentation is heterogeneous with many disparate data types and experiments that need to be coordinated sometimes from different sites, countries or continents

• Groups involved are having difficulties accessing all relevant data in a timely manner and then analyzing it.

• Report creation is cumbersome and time consuming

Unified Laboratory IntelligenceManaging the Data

CrystallizationConditions Casual users

FilesImagesStructures Metadata

XRPD

DSC, HPLC, …

View Experimental Data

Clustering

Clustering

Analysis/Review

Compare each spectrum to the average for its group

Compare different clustering methods

Data Review

XRPD Overlays

Graph

Overlay Legend

Nearest Neighbors Table

DSC curve

TGA curve

Image

Supervision & Decision Making

Reporting

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1 48001 1 (XRAY Spectrum) 2 (CURVE Spectrum) 3 (CURVE Spectrum)

10 0.4840 0

2 4800217 2 (XRAY Spectrum)

10 0.4823 0

3 480039 3 (XRAY Spectrum)

16 0.4864 0

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Avg_HQI (ListA) where Supervised="0" (82 pts)Avg_HQI (ListA) where Supervised="1" (14 pts)

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Avg_HQI (ListA) where Supervised="0" (82 pts)Avg_HQI (ListA) where Supervised="1" (14 pts)

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#List # #ID Spec# XrpdID Avg_HQI Supervised

1 48001 1 (XRAY Spectrum) 2 (CURVE Spectrum) 3 (CURVE Spectrum)

10 0.4840 0

2 4800217 2 (XRAY Spectrum)

10 0.4823 0

3 480039 3 (XRAY Spectrum)

16 0.4864 0

Database: PostgreSQL DB on localhost <test96>, Record ID: 48025

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Summary

• One unified environment for multiple sources of data and multiple techniques Consolidation of data, IP protection if data are provided by third parties

• Data are minable by structure, substructure, meta data, spectrum,…. Then report is only a couple of clicks fast reporting to regulatory department

• Commercial off the shelf application to support the scientists’ decisions and for managing the workflow better throughput, wiser decisions,

• The solution is a part of a Unified Laboratory Intelligence strategy within the organization contributing to corporate knowledge management while also taking advantage of it