The Role of Microstructure in Topical Drug Product Development, 1st ed. 2019
AAPS Advances in the Pharmaceutical Sciences Series, Vol. 36

Coordinators: Langley Nigel, Michniak-Kohn Bozena, Osborne David W.

Language: Anglais

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390 p. · 15.5x23.5 cm · Hardback
Following the Semi-solid Microstructure Workshop sponsored by BASF and hosted by the Rutgers Center for Dermal Research, a pharmaceutical product development working group was formed. The group, known as the Q3 Working Group, selected the following five areas of focus:  Particle/Globule Size and Distribution,    Viscosity/Rheology/Spreadability, In Vitro Testing, State of API, State of Excipients. A committee was appointed for each of these five areas. The committees were tasked to review the literature, identify best practices, list experimental details required for an independent lab to duplicate the test, and propose scientific studies that may meaningfully advance this specific area of focus.  Each committee has a chair (or co-chairs) that are the lead author(s) of the chapter. The Q3 Working Group members serve as the critical reviewers of each chapter, making suggestions that improve the quality of the document and that make each of the five chapters uniform in scope and content.
Pharmaceutical development scientists that formulate topical products (creams, lotions, gels suspensions, foams, etc) and all the allied raw material suppliers, packaging suppliers, contract laboratories including CROs, CMOs and regulators need access to this book.  Overall, the topic of semisolid microstructure is of equal importance to the generic pharmaceutical companies (filing Abbreviated New Drug Applications or ANDAs) and pharmaceutical companies filing New Drug Applications (NDAs).  In addition to products applied to the skin, hair, and nails, The Role of Microstructure in Topical Drug Product Development? crosses over and is essential reading to developers of oral suspensions, ophthalmic ointments and gels, otic suspension, vaginal semisolids and retention enemas.


  Executive Summary / Scope


Chapter focuses on the following aspects of rheological properties of topical semi-solid formulations:

-         Analytical instrumentation and techniques to determine rheological properties.

-         Factors affecting rheological properties:

o   Formulation physical/chemical parameters (i.e., pH, concentration of excipients, excipient combinations, etc.)

o   Primary container closures

o   Manufacturing/process equipment

-        Review of current literature and recommendation on best practices for 1) characterizing the rheological aspects of topical semi-solid formulations during development phase and 2) rotational viscosity methods to ensure product consistency for commercial stage products.


2.     Background  

2.1.  Definitions

2.1.1.     Rheology, viscosity, thixotropy, rheopexy, viscoelastic behavior

2.2.  Why is rheology important for topical semi-solid formulations?

2.2.1.     Newtonian systems vs non-Newtonian systems

2.2.2.     Raw materials

2.2.3.     Formulations

2.2.4.     Effect of Processing parameters

2.2.5.     Quality Control

2.3.  Rheological Test Methods

2.3.1.     Continuous shear vs Oscillatory shear

2.4.  Instrumentation

2.4.1.     Viscometry: Single point vs Multiple point instruments

2.4.2.     Rheometry: Controlled stress vs Oscillatory Rheometers


3.     Review of current state and outline best practice  

3.1.  USP chapters 911,912 and 1911 and 1912

3.2.  Rheology of different dosage forms

3.2.1.     Creams

3.2.2.     Ointments

3.2.3.     Lotions

3.2.4.     Gels

3.2.5.     Others (foams, SLN dispersions etc.)

3.3.  White papers from instrument manufacturers

3.3.1.     Application specific analysis of rheology          Effect of temperature on viscosity          Effect of shear rate on moduli          Determination of yield stress

3.4.  Correlation of processing conditions to the rheological data

3.4.1.     Speed of mixing

3.4.2.     Processing temperature

3.4.3.     Others (use of vacuum, presence of nitrogen, mixing type – homogenizers, dispersers, propellers, spindle mixers etc.)


4.     Recommendation for next steps

4.1.  Identify gaps

4.1.1.     Temperature dependent studies          What is there to gain by evaluating the rheology of a semi-solid product at temperatures other than its recommended storage condition.

4.1.2.      How is viscosity data being used          What other variables of product development can viscosity/rheology be evaluated for other than physical stability.





Chapter outline:


A.     Introduction: Role of excipients with respect to the relationship between  Q1/Q2/Q3, quality attributes and product performance

1.      The semisolid state is a result of the formation of the microstructure driven by  several variables including excipient selection and quantity, processing variables, and storage time. This chapter will focus on the influence of excipients.  Excipients can be affected by processing

a.     Similarity of Q1/Q2 alone may or may not lead to similar or desired Q3 (microstructure) properties due to the influence of processing variables.

b.     Similarity of Q1 and Q2 and optimized process conditions necessary to achieve desired microstructure.


2.     Role of grade and/or quality of of critical excipients in achieving a similarity of Q3 (microstructure). (e.g. Emulsifiers, Thickeners, Emulsion Stabilizers, etc.)

a.     Defining what we mean by “grade”.

b.     Adequate characterization of critical excipients.

c.      Role of excipient specifications

B.     Literature review and lab data demonstrating the impact of excipients on Q3 microstructure of semi-solid dosage forms.


1.     How the different excipients play a role in the formation of microstructure

a.     Fatty alcohols and self-bodying systems


c.      PEG microstructure in PEG ointments

d.     Other examples

2.     Role of excipient selection in achieving desired Q3 (microstructure).

a.     Impact on in vitro release (IVRT) and in vitro skin permeation (IVPT)

b.     Impact on other finished product critical quality attributes or specifications (e.g. viscosity, appearance, pH, etc.)

C.    Role of grade and specifications of the excipients in the formation of microstructure Conclusion




Chapter outline:

A.     Introduction: in vitro testing (IVRT, IVPT) and correlation to Q3 microstructure


1.      Critical Quality Attributes (CQA) play an important role in demonstrating Q1, Q2 and Q3 equivalence of topical products. In vitro testing (IVRT, IVPT) is one of the CQAs that is predominantly used in the correlation of Q3 microstructure to product performance. This chapter will provide an introduction to in vitro testing and how this test can be a tool in evaluating Q3 microstructure.

a.      Background information on in vitro testing

o   Fick’s law and Higuchi principles

o   How does thermodynamic activity influence IVPT

o   Definition of and difference between IVRT and IVPT

o   Synthetic membranes versus skin, rate-limiting and non-rate limiting membranes

o   How drug is transported across different layers of skin

o   How skin permeation is influenced by formulation components – give examples

b.      in vitro as a Critical Quality Attribute

o   Introduction to Q1, Q2 and Q3 attributes

o   Role of in vitro testing in product development

o   How in vitro test can be used in QbD and defining critical process parameters (CPP)

o   SUPAC Guidance


2.      Typical semisolid dosage forms include gels, creams, ointment, and lotions and each of these has a different matrix that varies in complexity and affects the IVRT differently (cover aspects of the formulation such as the matrix that would affect release rate).

a.     Explain the different matrices in semisolid dosage forms

b.     Complexities of the matrices and role of formulation and process

c.      How IVRT is affected by the different matrices


3.      Various microstructure parameters influences the release rate that include

a.     Rheology (and viscosity)

b.     Globule and particle size

c.      pH

d.     phase homogeneity

e.     Others?


B.     Various types of excipients (or inactive ingredients) are used in semisolid formulations and each of them has a different functionality. The type and grade of excipients used has an influence on the microstructure properties.  This section will include the

a.      Different grade/type of excipients

b.      Different solvents, co-solvents, permeation enhancers

c.      Preservatives, coloring agents, fragrances

d.      How the type and grade of excipients influences the microstructure and release rate


C.    IVRT as a tool in Quality by Design

The FDA is giving significant importance lately to Design of Experiments (or Quality by Design) in the development of topical products as changing some parameters such as the order of addition and process parameters are designed can change the microstructure and hence the product performance. IVRT is used as an important tool in the Quality by design studies and this section will provide insight into how a combination of microstructure characterization and IVRT can help in the QbD study design.

a.     Order of addition

b.     Dissolution rate

c.      Mixing speed and time

d.     Homogenization

e.     Mixing temperature


D.    Microstructure properties are greatly influenced by the Critical Process Parameters (CPP) on microstructure and release rate. IVRT is one of the key CQAs that is used in evaluating the critical process parameters during product development such as

a.     Rate and mechanism of addition/ reduction

b.     Mixing time

c.      Cooling/heating

d.     Mixer type – dispersion, sweep and homogenizer

e.     Mixing Temperature, speed and duration

f.       Hold times at various process steps

This section will highlight the importance of how IVRT can help in correlating microstructure with the critical process parameters.

E.     Post approval changes and IVRT

IVRT plays a very important role in evaluating any post-approval change in process that can impact product quality and performance. FDA has issued the SUPAC-SS guidance to identify the different levels of process changes and how IVRT should be conducted to evaluate the impact. This Section will detail the various process level changes and what methodology should be adopted.





Chapter outline:


1.     Introduction

State of API is one of the critical quality attributes of topical dosage forms. Molecular and solid-state properties of the API are important determinants.

1)     Molecular attributes of API

                                                    i.     Molecular size

                                                   ii.     Partition coefficient

                                                  iii.     Solubility

                                                 iv.     Ionization

                                                   v.     API property space for topical formulations: “Rule of N”

2)     Introduction to Polymorphism

a)     Definitions (scientific, regulatory, legal, etc.)

b)     Thermodynamics of polymorphs

c)     Properties that can vary with solid forms (melting point, hygroscopicity, dissolution, etc.)

3)     Other physical forms (solvates, hydrates, clathrates, disordered phases)

4)     Additional systems

                                                    i.     Salts/co-crystals

                                                   ii.     Prodrugs

                                                  iii.     Soft drugs

                                                 iv.     Supersaturated systems

                                                   v.     Nanoproducts

2.     Analytical techniques for physical characterization

Adequate characterization and understanding of state of API is a key component to successful formulation development. Characterization can involve qualitative or quantitative determination of forms.

1)     Identification

                                                    i.     X-ray Powder Diffraction (XRPD)

                                                   ii.     Spectroscopy (Raman)

                                                  iii.     Thermal methods (DSC/TGA/HS-microscopy)

                                                 iv.     Optical Microscopy

                                                   v.     Others (ssNMR, SAXS, synchrotron X-ray)

2)     Quantification

3.     State-of-API-related risk assessment and mitigation for topical dosage forms

1)     Criticality of state of API

2)     Processing-induced form transformation

3)     Physical stability during storage

4.     Considerations and Best practice for state of API Q3

1)     Analytical considerations

2)     Regulatory considerations

3)     Best practice

5.     Conclusion




Chapter outline:

Introduction and Scope

Microscopic View-Optical Microscopy

            -Polarized Light Microscopy (PLM) to determine suspended API particle size and distribution

            -Optical microscopy of emulsions

                        Determination of globule size and distribution

                        PLM Microscopic View of liquid crystal stabilized emulsions

            -Particle characterization of topical products using image analysis

Particle characterization using light scattering/diffraction

Particle characterization using Morphologically Directed Raman Spectroscopy (MDRS)

Particle characterization using cryo-scanning electron microscopy (SEM).


Based on findings from a pharmaceutical product development group arising out of the 2016 Semi-solid Microstructure Workshop sponsored by BASF and hosted by the Rutgers Center for Dermal Research

Presents five crucial areas in semi-solid microstructure topical drug product development

Reviews the literature

Identifies best practices

Lists experimental details necessary to duplicate the tests

Identifies scientific studies that advance the subject areas