A SEMINAR ON APPLICATIONS OF VARIOUS ANALYTICAL TECHNIQUE

A seminar on applications of various analytical technique used in Preformulation study and its importance:

Prepared By: Mr. Ankit R. Parmar M. Pharm , Sem –II Q. A. Department-SJTPC Guided By: Mrs. Parula B. Patel Head of Q. A. Department-SJTPC, Rajkot A seminar on applications of various analytical technique used in Preformulation study and its importance . . 1

Content::

Introductions Overall industrial Program Need for a Preformulation Study Preformulation Study in Support of New Drug Product Development Stages of Preformulation Studies Preformulation Report Analytical techniques and instruments for preformulation studies Regulatory requirements for preformulation Appendix 1: physicochemical properties and analytical testing for drug substance Appendix 2: data for supporting development of solid dosage forms Appendix 3: support for quality control and finished product manufacturing Questions asked in GTU Reference Content: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 2

Introductions::

Definition: “ Preformulation study is define as the process of optimizing the delivery of drug through determinations of physicochemical properties of the new compound that could affect drug performance and development of an efficacious, stable and safe dosage form.” Preformulation is the study of the chemical and physical properties of the drug components prior to the compounding process of the formulation. The purpose of the study is to understand the nature and characteristics of each component and to optimize conditions of the dosage form manufacture. Introductions: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 3

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Goal: Establish the identity and physico - chemical parameters of a new drug substance. Establish its kinetic rate profile. Establish its physical characteristics. Establish its compatibility with common excipients . . 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 4

Overall industrial Program: :

The birth of new drug substance and its eventual marketing following events take place between the birth of a new drug substance and its eventual marketing; The drug is synthesized and tested in a pharmacological screen. The drug is found sufficiently interesting to warrant further study. Sufficient quantity is synthesized to Perform initial toxicity studies. Do initial analytical work and Do initial preformulation. Overall industrial Program: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 5

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Once pass initial toxicity phase I (Clinical pharmacology) begins and there is a need for actual formulations (although the dose level may not yet be determined). Phase II and Phase III clinical testing then begins and during this phase the formula is finalized. After completion of the above, an NDA (New Drug Application) is submitted. After approval of the NDA, Production can start (Product launch). . 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 6

Need for a Preformulation Study::

Establishment of drug specifications intended for toxicological evaluation and clinical supply preparations. Formulation of clinical supplies and establishment of their preliminary specifications Providing scientific data to support dosage form development and evaluation of product efficacy, quality, stability, and bioavailability Evaluation of the stability of early developed dosage forms Fulfillment of the requirement of the CMC section of the IND and subsequent NDA or ANDA Need for a Preformulation Study: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 7

Preformulation Study in Support of New Drug Product Development::

A typical development track activity for preformulation monitoring may be divided into several phases, as discussed in the following. Selection of a Drug Substance for Dosage Form Development : Structure Modifications In many instances, modification of the chemical structure or physical property may prove to optimize the therapeutic and pharmaceutical values of the candidate. Preformulation Study in Support of New Drug Product Development: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 8

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Purity The purity profile must be established, and quality consistency must be enforced. Chirality Chirality is the existence of different configurations of a substance with an identical chemical structure. This substance may be resolved into enantiomers with nonsuperimposable mirror images. In addition to physiological activities, stereospecificity influences the physicochemical properties of drugs. 11 July 2011 9 by A. R. Parmar-SJTPC, Rajkot .

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Salt Forms Selection Many synthetic substances to be used in solid dosage form are too limited in solubility to be therapeutically effective. The desirable solubility for an oral solid is suggested to be more than 1 mg/ml (0.1%). Prodrugs For example, the solubility and dissolution rate of the n- hydroxymethyl derivative of lomefloxacin is higher than those of the parent compound, and it can be converted readily back to the original molecule. Commonly used Prodrugs are procaine penicillin metronidazole phosphate and chloramphenicol sodium succinate. 11 July 2011 10 by A. R. Parmar-SJTPC, Rajkot .

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Metabolites The metabolism study of a drug candidate should be carried out in the earlier stage of development soon after the selection process. The major metabolites should be tested pharmacologically and toxicologically against the candidate. If similar profiles are found, consideration should be given to replacing the original drug candidate with its metabolite. Intellectual Property Protection and Patent Filing Selection of Analytical Technique and Development 11 July 2011 11 by A. R. Parmar-SJTPC, Rajkot .

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Preparation and Submission of IND Clinical Trial Studies Development and Manufacturing of Dosage Forms Establishment of a QA/QC System Preparation of a New Drug Application Abbreviated New Drug Application . 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 12

Stages of Preformulation Studies::

The preformulation is performed in several stages with different development cycles, which are discussed in the following. Preformulation Report, Part 1: Physicochemical Properties and Analytical Testing for Drugs Preformulation Report, Part 2: Data Supporting the Development of Dosage Forms Preformulation Report, Part 3: Support for Quality Control and Finished Product Manufacturing Stages of Preformulation Studies: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 13

Preformulation Report::

Analytical Profiles (Required for Analytical Method Development) Identification of Drug Substance Purity Absolute Purity Chemical Properties Thermodynamic and Physicochemical Properties Dissociation Constant, pKa Solubility Method of Solubility Determination Solubilization Preformulation Report: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 14

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Pharmaceutical and Mechanical Properties Hygroscopicity and Moisture Absorption/Desorption Powder Characteristics Mixing and Blend Uniformity Solid-State Characteristics Polymorphism Hydrates and Solvates (Pseudomorphism) Amorphous Powders Morphology, Size, and Surface Area . 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 15

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Biopharmaceutical Properties Partition Coefficient Permeability in the GI Tract Dissolution Rate and its in vivo–in vitro Correlation Excipient Compatibility Studies Stability . 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 16

Analytical techniques and instruments for preformulation studies::

A preformulation study is performed to gain insight from physicochemical and biological data into the design and development of dosage forms. Samples are taken in each study and analyzed qualitatively and/or quantitatively, according to the need. Analytical techniques are generally divided into two prevalent areas in the specific detection and separation sciences. Analytical techniques and instruments for preformulation studies: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 17

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Specific Detection Specific detection is an analytical determination based on specific responses related to the chemical characteristics of a molecule excited by a certain type of irradiation. In this detection method, measurement of the molecule of interest may usually be performed without separation from matrix materials or from other ingredients if appropriate instrumental adjustments are made. Techniques such as Fourier transform IR (FTIR), attenuated total reflectance (ATR), NIR, Raman spectroscopy are used with increased regularity. . 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 18

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The detection of foreign metal contaminants is essential with inductively coupled plasma spectroscopy (ICP), atomic absorption (AA), and X-ray fluorescence. Also notable is the increased attention to analysis of chiral compounds, as in the synthesis of drug substances. Optical rotation, ORD, and CD are currently the preferred instruments for this practice. . 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 19

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The analytical techniques commonly used in the preformulation study are: UV Spectroscopy UV absorptions are mainly electronic in nature and are associated with resonating structures in the molecule. The UV quantitative determination, generally performed in solution, is based on the Beer–Lambert law. In a preformulation study, solubility, dissolution rate, and some stability studies (when degradation products have a different absorption maximum from the parent compound) are performed with the UV technique. Visible Photometry and Colorimetry . 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 20

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IR Spectroscopy IR spectroscopy is used extensively in pharmaceutical analysis for fingerprint identification of a drug molecule and the proof of its structure. IR absorption bands are characteristic of the functional group of a molecule as well as the structure configuration. The wavelength of the IR spectrum is 750–2500 μm . The sampling preparation techniques for IR determination are solution, drug dispersion in a KBr pellet, Nujol mulls, and direct determination by microscopic ATR preparation. An example of modern IR equipment is FTIR, which gives better quality determination. 11 July 2011 21 by A. R. Parmar-SJTPC, Rajkot .

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Raman Spectroscopy Raman spectroscopy is based on the phenomenon of inelastic light scattering. When a particle is irradiated at a certain frequency, radiation scattered by the molecule contains photons of the same frequency as the incident radiation and may contain photons (weak signal) with a changed or shifted frequency. Raman spectroscopy is a nondestructive tool and requires little or no sample preparation. A sample may be analyzed in solid or powder form or in an aqueous solution and placed in glass containers such as an NMR tube, GC vial, test tube, light-path cell, or glass bottle. Aside from structure elucidation and functional group analysis, FT-Raman may be used for quantitative determination of polymorphs in a preformulation study. 11 July 2011 22 by A. R. Parmar-SJTPC, Rajkot .

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NIR Spectroscopy NIR is making significant progress through recent advances in pharmaceutical analysis. The advantage of this technique is the rapidity of analytical determinations without sample preparation and the use of solvent. The NIR spectrum is primarily related to the overtone variation. Hence, the absorption bands are generally weaker than those in the IR. The wavelength of the NIR spectrum is defined as 2500–3000 μm . The detection method is nondestructive. Therefore, it is suitable for use in on-line monitoring and meets 100% inspection requirements in quality control practice. 11 July 2011 23 by A. R. Parmar-SJTPC, Rajkot .

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X-Ray Diffraction The X-ray diffractometry technique obtains information on substance structure at the atomic level. This technique allows measurement of both crystalline and noncrystalline materials. The analysis is nondestructive in nature and handles samples in the form of powders, solids, and liquids. The X-ray diffraction of a single crystal is employed for the determination of the absolute chemical structure. Quantitative ratios of two polymorphs and their percentage of crystallinity may also be determined. 11 July 2011 24 by A. R. Parmar-SJTPC, Rajkot .

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NMR Spectroscopy NMR involves the absorption of electromagnetic radiation in the radiofrequency of a longer wavelength spectrum. When a sample is placed with atomic nuclei of hydrogen (1H, protons), fluorine (15F), or phosphorous (31P) in a magnetic field, absorption of energy will occur. The nuclei shift from the preferred orientation with lowest energy to a less preferred, high-energy orientation at a particular frequency. Thus a plot of frequency versus intensity of radiation results in the NMR spectrum of a material. Spectra of NMR can be obtained in liquids or in solids . 11 July 2011 25 by A. R. Parmar-SJTPC, Rajkot .

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Mass Spectrometry Metal Analysis X-Ray Fluorescence Atomic Absorption 11 July 2011 26 by A. R. Parmar-SJTPC, Rajkot .

Separation Sciences:

Thin-Layer Chromatography High-Pressure Liquid Chromatography Capillary Electrophoresis Gas Chromatography Ion Chromatography Supercritical Fluid Chromatography Separation Sciences 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 27

Thermal Analytical Methods:

Equipment for thermal analysis is used extensively for the preformulation study. As in the solid-state investigation, interest is focused not only on the chemical change but also on the physical change, which can be illustrated appropriately by thermometric methods. Differential Scanning Calorimetry Hot Stage Microscopy Thermal Gravimetric Analysis Solution Calorimetry Thermal Analytical Methods 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 28

Regulatory requirements for preformulation::

Regulatory Compliance FDA initiatives and other government regulations influence pharmaceutical manufacturing operations, including preformulation studies and quality control systems. These regulatory issues include the topics outlined below: Regulatory requirements for preformulation: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 29

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Current Good Manufacturing Practices The cGMP is an FDA mandatory quality program designed to ensure that pharmaceutical products are consistently produced and controlled according to the quality standards appropriate to their intended use. The cGMP was originally developed for the dosage form or finished product and for bulk drug substances in the absence of a published guideline. . 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 30

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Good Laboratory Practice In contrast to cGMP, which regulates manufacturing and its related quality control activities, good laboratory practice (GLP) covers research activities. The most significant difference between the two sets of guidelines is in the requirements of archiving for test samples and data. GLP regulates all nonclinical studies and was originally intended for toxicity testing only. The requirements of analytical measurements and methods in support of toxicological studies are included in the GLP . 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 31

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International Conference on Harmonization The ICH is intended to avoid duplication efforts for product registration and manufacturing in world trade. Quality Control for a Preformulation Study Personnel Qualification and Training Analytical Method Validation Documentation and Standard Operating Procedures . 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 32

Appendix 1: physicochemical properties and analytical testing for drug substance::

Appendix 1: physicochemical properties and analytical testing for drug substance: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 33

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Appendix 2: data for supporting development of solid dosage forms::

Appendix 2: data for supporting development of solid dosage forms: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 38

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Appendix 3: support for quality control and finished product manufacturing::

Appendix 3: support for quality control and finished product manufacturing: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 42

Questions asked in GTU::

Explain preformulation study. Give its importance. Describe thermodynamic and physicochemical properties in preformulation study. ( 8 marks ) - 2010 Give brief review of analytical methods used in preformulation study. ( 8 marks ) - 2010 Questions asked in GTU: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 43

Reference: :

Dr. Javed Ali, Dr. R. K. Khar , Dr. Alka Ahuja , Dosage form design, 5 th edition, Page no. 01 – 30. Satinder Ahuja and Stephen Scypinski , Handbook of Modern Pharmaceutical Analysis, Vol. 3, Page no, 172 – 233. Reference: 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 44

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. . Thank you 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 45

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. . Any questions ? 11 July 2011 by A. R. Parmar-SJTPC, Rajkot 46