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API CRYSTALLIZATION AND FORMULATION SOLUTIONS FOR TODAY’S DRUG DEVELOPMENT NEEDS

INTRODUCTIONCrystallization of active pharmaceutical ingredients (API) and related pre- and early formulation development play critical roles in successful drug development and manufacturing. The associated challenges can create signifi cant roadblocks in the production of APIs and drug products as well as complicate regulatory fi lings in early pharmaceutical development (fi gure 1). A professional team with scientifi c rigorousness and comprehensive expertise is in urgent demand in the space of contract research organizations (CRO) and contract development and manufacturing organizations (CDMO) for today’s fast-paced and integrated drug development.

The Center for Pharma Crystallization (CfPC) in J-Star Research, a contract research and development organization, was created to meet this demand. Both small and large pharmaceutical companies need to address a wide range of API crystallization and pre- and early formulation challenges for their drug development programs. For virtual or small drug developers with no or limited internal R&D expertise, CfPC helps get new drugs to Phase I faster by discovering solid forms of API and intermediates, evaluating and selecting or recommending

API molecule API crystals Drug product

Typical critical quality attributes

▶Purity (potency, impurities, residual solvent, etc.)

▶Solid form (polymorph, hydrate/solvate, salt, cocrystal, amorphous phase)

▶Particle attributes (size distribution, density, hygroscopicity, morphology,

color, caking/sticking, specific area, etc.)

▶Stability(chemical and/or physical)

BioavailabilityEcacySafety

Figure 1

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suitable forms for formulation development, developing crystallization processes with proper control of critical quality attributes (CQAs), and designing and developing drug substance-drug product (DS-DP) coprocessing to meet formulation needs with desired quality control. For large pharma companies with strong in-house R&D, CfPC can identify missing or undiscovered crystalline forms for patent protection and process optimization, optimize fi nal isolation processes and defi ne critical process parameters and their proven acceptable ranges. CfPC also can identify CQA control strategies for robust scale-up to manufacturing, and develop improved formulation via well-engineered DS-DP coprocessing (fi gure 2). A uniquely integrated team of experienced chemists and engineers with comprehensive technical backgrounds was assembled to offer unparalleled and nonbiased solutions for small or large drug developers.

BUILDING QUALITY INTO THE CRYSTALLIZATION PROCESS Crystallization processes, especially for fi nal API isolation, serve as quality-control steps for API products. These processes should be designed and controlled to meet predefi ned product quality attributes to ensure the safety and effi cacy of the fi nal drug product as required by government regulators.1 But even today, many chemists and managers in the pharma industry regard crystallization processes as more of an art than a science. CfPC takes the opposite view. It believes that rigorous application of relevant scientifi c and engineering principles to each aspect of the crystallization process not only builds in quality but also increases the effi ciency and stability of the process itself (fi gure 3).

Good process understanding is key to these efforts. Achieving this understanding enables the right process design and control to meet predefi ned CQAs of the product. For example, CfPC has frequently been called on to address the problem of “oiling out” during the crystallization process—a major headache for API process development. In one case, an API needed to be isolated into three different anhydrous polymorphs, but all of them encountered an oiling-out issue during process development elsewhere. Finding solutions started with the collection

API synthesis

Formulation

Solid-form discovery and studies

Crystallizationprocess development

Product quality

Process robustness

Drug development e�ciency

Pre- and early formulationdevelopment

DS-DP coprocessing

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FO

R P

HA

RM

A C

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ST

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Figure 2


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of phase boundary data for respective solvent systems within practical ranges of critical processing parameters. Analysis of these data allowed CfPC to quickly defi ne the process space for each polymorph that prevented oiling out while simultaneously addressing additional challenges, including control of particle size distribution (PSD) and yield maximization. The fundamental understanding gained about the compound/polymorph/solvent system ultimately sped up the process development, enabled robust process control, and increased the yield of delivery batches for the drug’s formulation development.2 Such challenges get addressed effectively via the approach taken by CfPC.

A common demand for fi nal API crystallization process is to meet specifi cations of particle attributes, such as PSD, crystal morphology or shape, and bulk density. For example, during early drug development, API crystals with different PSDs are often prepared for preliminary formulation evaluations. Once the desired PSD range is defi ned or selected, the API manufacturing process must be able to consistently produce the same PSD in every batch of product. Both early API deliveries with different PSDs and robust manufacturing of drug substance meeting target PSD face technical challenges and resource constraints in development.

Preventing the generation of undesired forms during API processing has long been a top priority for drug developers and manufacturers. A good understanding of the thermodynamics and kinetics of a specifi c (polymorphs/solvents) system is essential to designing the right process in the fi rst place or to solving problems that arise during process development, scale-up, and technology transfer. For crystallization processes developed elsewhere, CfPC scientists have quickly addressed multiple cases of late appearance of a new polymorph via accurate measurement of solubility profi les and metastable-zone width data. The right fundamental data enable right solution to the challenging problem.

To better understand and control the crystallization processes, real-time in-process information is monitored and analyzed by process analytical technologies (PATs). Focused beam refl ectance measurement, BlazeMetrics, process Raman, and ReactIR are applied by CfPC scientists during process development. Use of these

Solvent/Base/Acid Screening & Selection

Information Gathering & Evaluation

Thermodynamic and Kinetic Data (Profiles)

Process Design, Testing & Optimization CPPs Evaluation and PAR Study

Control Strategy/Eng. Implementation

Process Demonstration

Tech Transfer

Robust and Efficient Crystallization Processes

Product Quality

Solid Form Purity

Residual Solvent Level

Chemical & Physical

Stability

Particle Attributes

Crystal Size Distribution

Chemical Purity

Science & Engineering Reproducibility ! Consistent Product Quality

suggested Figure 3


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tools facilitates the collection of valuable information from limited experiments that are otherwise diffi cult to achieve. For instance, using the imaging capability of BlazeMetrics, the latest PAT tool, CfPC experts quickly discovered the hidden complication in isolation of a target crystal form. A metastable form generated in an earlier part of the process was detected by both images and Raman signal via BlazeMetrics before conversion into the more stable target form later. Such information facilitates the process optimization with unmatched effectiveness.

“CURING” THE PAINS CAUSED BY FORMS Timely discovery, identifi cation, and selection of a suitable solid form for an API (fi gure 4) or its intermediate(s) are essential for process development, formulation design, and regulatory fi ling.3 Drug developers encounter various problems caused by polymorphism of the API and/or intermediate molecules (fi gures 4 and 5) that can affect the entire development of a drug candidate, many aspects of its manufacturing and commercialization, and even the life cycle and future of a drug after launch. As evidenced by the ritonavir story,4 an unexpected form change can trigger long-term repercussions for both commercialization of a new drug and the patients who depend on the drug for treatment.

Crystalline

Drug substance (API)

Semi-/noncrystallineFree form | Hydrates/solvates

Salts | Cocrystals Gel/liquid crystals | Partial crystalAmorphus

Pre-/early formulation

Stability | Solubility | Dissolution | Absorption | Partical attributes | Processibility | Others

Glass transition and solid dispersionPolymorphism and

interconversion

Figure 4

Figure 5

Di�erent API solubility � failing formulation � product withdrawal

Competitor can take advantage � losing market share

Change target form � more formulation development � drug development program delay

Di�erent impurity rejection power � product purity failure

Forming undesired solvate � failing residual solvent spec

Undesired bulk API properties � challenging post processing

Undesired salt disproportion � failing product stability

Polymorphs of similar solubility � demand for tight process control

Di�erent particle properties � inconsistent filtration/drying � failing CQA specs

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Researchers have widely accepted that discovery, identifi cation, and selection of different solid forms are critical to a drug’s success and should be conducted early in drug development. Using state-of-the-art instrumentation and an integrated approach, CfPC’s expert staff is able to discover potential forms of APIs and intermediates through well-rationalized, detail-observant, and results-oriented screening and characterization. Drug developers reap the benefi ts of the team’s expert ability to identify and understand the desired properties and applications of these forms for successful drug substance and product developments.5

Crystallography is another means by which CfPC analyzes and solves problems encountered in the course of API process research, development, and manufacturing. Crystallography provides precise measurements of structural properties with a degree of accuracy that no other method can approach (for example, absolute confi guration and conformation). Determining the structural properties of a compound provides valuable information about its molecular behavior and the reactivity and stability of its solid forms. The structural insight gained also helps researchers devise solutions to problems encountered during processes such as purifi cation via crystallization, fi ltration, and drying. Although growing single crystals of many pharmaceutical compounds and intermediates can be daunting, CfPC scientists help drug developers overcome these diffi culties. For example, solvates are typically not ideal as a fi nal isolation form, but certain solvates with good structural arrangement can afford desired purifi cation power. This can add tremendous value to the synthetic route of an API. By discovering, understanding, and using such solvates, CfPC has helped eliminate potential problems caused by impurity control for several developmental APIs.

OVERCOMING FORMULATION HURDLESEvaluation and selection of solid forms for an API also reduces the risk of possible formulation issues arising in future development. With successful API form screening and isolation process development, selection of the right solid state and strategy for pre- and early formulation studies aligns closely with both a fundamental understanding of the drug compound and fi t-for-purpose demand for development of the drug product.

Early formulation development requires integration of API properties (such as crystallinity and form transformation) with drug product design (such as solubility, dissolution and stability). At CfPC, the form screen and selection criteria incorporate attributes of the API as well as the demands of formulation requirements. For example, the form screen for insoluble drugs includes both crystalline (hydrates, solvates, salts, and cocrystals) and noncrystalline (amorphous-state) phases.6 Additional enabling technologies, such as amorphus solid dispersions for increased solubility and dissolution,7 are also applied in early formulation development to improve the effi cacy and bioavailability of drug candidates (fi gure 4).


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With meticulous planning, CfPC anticipates that potential concerns may occur throughout all stages of pre- and early formulation development, as shown by toxicology and pharmacokinetics (tox/PK) and fi rst-in-human (FIH) service (fi gure 6). This approach allows CfPC to strategize solutions and contingencies for most of the critical events that may be encountered during formulation research and regulatory phases. For this purpose, the development of an API at CfPC is aimed at not only improved properties of drug compound but also synchronized support for formulation design and progress at various stages of drug development.

BRIDGING THE GAP BETWEEN API AND DRUG PRODUCT DS-DP coprocessing is used extensively at CfPC to align both API and drug product development and to overcome potential hurdles in drug development (fi gure 7). In solid-dosage processes, the API is generally blended with excipients via wet or dry granulation. Coprocessing is a relatively new area of particle engineering in which commonly used excipients can be combined with the API in a more deliberate and controlled manner to design a pharmaceutical composite material.8,9 This approach combines two or more materials in a specifi c way to produce a composite material with improved physical or chemical properties. A process can be designed to resolve some of the common issues related to solid-dosage production, such as material fl ow, stability, compactibility, release profi le, bioavailability, food effect, content uniformity, taste, and even containment issues related to potent or toxic compounds.

At CfPC, crystallization efforts and form selection of APIs are closely integrated with the requirements of overall product development. As an example, for amorphous compounds, the end-point API is an intermediate coprocessed in a dispersion with suitable formulation excipients to provide enhanced physical and chemical properties, such as stability, fl ow, and bioavailability, as evidenced by increased solubility and dissolution.10

Pre- and early formulation

Toxicology/Pharmacokinetics First-in-Human Trial

Single-dose pharmacokinetics

� Basic properties� Risk assessment

� Exposure optimization

Multiple-dose pharmacokinetics

� Dose range� Phase selection

� Enabling technology� Stability

FIH

� Alignment of DS-DP development� Regulatory safety

� PK linearity� DP stability

Good Laboratory Practice (GLP) toxicology study for Investigational New Drug Applications

� Finalizing phase and formulation

� Process and analytical� Use-time stability

Figure 6

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CONCLUSIONChallenges associated with crystallization of a developmental API and its intermediates can be addressed effectively by a strong and high-performing service organization that supports each stage of drug development. The comprehensive R&D services provided by CfPC are aligned seamlessly with scientifi c and technical rigor and developmental synergies among crystallization process development, solid-form discovery and studies, pre- and early formulation studies, and DS-DP coprocessing. CfPC meets the demands of today’s pharmaceutical industry by anticipating, diagnosing and fi xing crystallization related problems during all phases of drug development with both APIs and drug products.

POOR

� Spray-dried dispersion

� Hot-melt extrusion

� Soft-gel capsule

� Hard-gel capsule

� Solubilized tablet

BIOAVAILABILITY INPUT FROM DISCOVERY

STABILITY DL

DL

CHEMICAL/PHYSICAL

ADEQUATE

DRUG LOAD (DL)

ADEQUATE

ADEQUATE

DL > 1%

POWDER PROPERTIESFLOW, DBULK

API AS IS

POOR

SOLUBILITY

POOR

DL > 25%

POOR

DL < 25%(Dry granulation)

DL > 50%

ADEQUATE(Spray granulation)

DL < 50%(Wet granulation)

DL 1% COPROCESSEDINTERMEDIATE

(CPI)

*DL = Drug Loading

Figure 7

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References1. Cerulean Associates, Why Quality by Design? An Executive’s Guide to the FDA’s Quality by Design, March 2008,

https://ceruleanllc.com/wp-content/articles/eReport_QbD_Executive_Guide_CERULEAN.pdf.2. Food & Drug Administration, Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations,

September 2006, https://www.fda.gov/downloads/Drugs/Guidances/UCM070337.pdf.3. Tandon, Runjhun et al., “Patenting of Polymorphs,” Pharm. Pat. Anal. 7, No. 2 (2018): 59–63.4. Bauer, J. et al., “Ritonavir: An Extraordinary Example of Conformational Polymorphism,” Pharm. Res. 18, No. 6 (2001):

859–866. 5. Sun, Changquan Calvin, “Materials Science Tetrahedron—A Useful Tool for Pharmaceutical Research and Development,”

J. Pharm. Sci. 98, No. 5 (2009): 1671–1687.6. Bates, S. et al., “Analysis of Amorphous and Nanocrystalline Solids from Their X-ray Diffraction Patterns,” Pharm. Res. 23,

No. 10 (2006): 2333–2349.7. Newman, Ann et al., “Amorphous Solid Dispersions: A Robust Platform to Address Bioavailability Challenges,”

Ther. Delivery 6, No. 2 (2015): 247–261.8. Saffari, Morteza et al, “A Novel Formulation for Solubility and Content Uniformity Enhancement of Poorly Water-Soluble

Drugs Using Highly-Porous Mannitol,” Eur. J. Pharm. Sci. 83 (2016): 52–61.9. Yazdanpanah, Nima et al., “Continuous Heterogeneous Crystallization on Excipient Surfaces,” Cryst. Growth Des. 17, No.

6 (2017): 3321–3330.10. Qian, F. et al., “Drug–Polymer Solubility and Miscibility: Stability Consideration and Practical Challenges in Amorphous

Solid Dispersion Development,” J. Pharm. Sci. 99, No. 7 (2010): 2941–2947.

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