Pre-formulation an Overview

Kh.Hussan RezaAsst. Professor , Dept of Pharmaceutics.

Bengal School Of Technology , Sugandha Hooghly,West Bengal

About…

• Khandekar Hussan Reza, M.Pharm• Has 4 years of teaching and 2 years of Industrial

experience in Fr&D.• At present Assistant Professor at Bengal School Of

Technology, Hooghly, West Bengal, India.• Currently is a part of an Industrial project on Oral thin

film.• Formulation development , mainly Preformulations and

QbD are his major area of interest• Email: hassan23pharma@gmail.com

Initial Concept..

• Stages of drug development: • Candidate selection preformulation Biopharmaceutics & Pdt Development

Optimization Commercialization.• Definition: (M.J.Akers , 1976): “Pre-formulation testing encompasses all studies

enacted on new drug compound in order to produce useful information for subsequent formulation of stable biopharmaceutical suitable drug dosage form.”

• Jim Well’s: Pharmaceutical Preformulations: The Physico-Chemical Properties of drug substances.

• Pharmaceutical R&D: “ CONVERT IDEAS INTO DRUG CANDIDATE FOR DEVELOPMENT”

• Pharmaceutical Fr&D : “ CONVERT CANDIDATE DRUGS INTO PRODUCTS FOR DEVELOPING COMPOUNDS”

Cont.• 1/ 5000 to 1/10000 compounds synthesized or developed reach market• 1/5 to 1/10 molecules selected for formulation finally move for

registration.• 3/10 molecules in market give fair return. ( poor activity / poor

formulation development)• For sustaining of product proper intensive pre formulation studies should

be done. • NB: As per survey McKinsey & Company –

6 months product delay reduce 1/3 of potential profit for product life time. 50% overspend on development cost reduce profit by 3.5% 9 % overspend on production cost reduce profit by 22% .

• Need for proactive Preformulations and formulation development:

Average time for product lunch is 10-12 years with a patent lapse of 20 years . Mergers , acquisitions – job loss as the primary patent of NCE expire. Diversity in global market : Europe, US, Japan. Cost of goods target : 5 to 10 % of finished product. Environmental pressure : Ban of CFC as per Montreal Protocol.

• Solution: Effective product life cycle management- lowering time frame of drug discovery( initiation of Preformulations and

formulation studies at candidate selection phase) increasing patent protection by reintroduction of process and product patent.

Candidate For Drug Selection

• Formulation Synthesis Factor• Formulation factor• Biopharmaceutical Factor: Route of

administrations.

Preformulation study begins during lead optimization phase (LO, for 2 years) and in parts during lead identification (LI) and Pre-

nomination (last 6months of LO)

Preformulation testing criteria • Pharmacological and toxicological study is not sufficient to decide the suitability of

lead compound.• Also involve physico-chemical characterization of solid and solution properties of

compound.• Delivery of drug from the formulation under suitable environment with reasonable

shelf life at room temperature showing sufficient bioavailability without food and drug interaction.

• Performing studies during Lead Optimization (LO) with minimum compound for the assesment of physico-chemical behavior, solubility, salt screening, solid state characterization.

• pKa Determinations.• The Partition and Distribution Coefficients

(log P and log D).• Initial Solubility.• Initial Stability: Solid State and Liquid State.• Solid state analysis.• Salt selection.

• Hygroscopicity: Dynamic Vapour Sorption (DVS) Isothermal Microcalorimetry• Thermal Analysis: Differential Scanning Calorimetry Modulated Differential Scanning Calorimetry Hot Stage Microscopy Thermogravimetric Analysis• Infrared (IR) Spectroscopy• X-Ray Powder Diffraction• Phase Solubility Analysis• Solution Calorimetry• Intrinsic Dissolution• High Performance Liquid Chromatography

• 1985, the U.S. Food and Drug Administration (FDA) indicated (The Gold Sheet) that the principal physicochemical techniques (in their approximate order of usefulness) that could be used to characterize polymorphs.

melting point (hot stage microscopy); infrared spectroscopy; XRPD; thermal analytical techniques (e.g., DSC, differential thermal analysis

[DTA], TGA,etc.) solid-state Raman spectroscopy crystalline index of refraction phase solubility analysis; solution-pH profile determination; solution calorimetry; and comparative intrinsic dissolution rates.

In-vitro and in-vivo trials

• Objective is to obtain and verify desirable drug delivery properties for a pharmaceutical formulation.

Characterisation of relevant physicochemical, pharmacokinetic/dynamic prerequisites provided by the drug molecule

Identification of the relevant biopharmaceutical targets and hurdles in formulation development

Definition of test methods/study designs needed to obtain the biopharmaceutical targets in the formulation development and correct interpretation of the study results obtained.

• Uses of different biopharmaceutical test methods in formulation development:

in vitro dissolution testing, bioavailability studies, in vitro/in vivo (IVIVC) correlation of drug dissolution, use of animal models in in vivo studies of formulations in vivo imaging of formulations by gamma scintigraphy.

IN VITRO DISSOLUTION• Investigation of drug release mechanisms, especially for ER formulations• To obtain a predefined target release profile and robust formulation

properties regarding influences of physiological factors (e.g., pH and food) on the drug release

• Generation of supportive data to bioavailability studies as an aid in interpretation of in vivo results

• Validation of manufacturing processes• Investigation of effects of different storage conditions• Batch quality control (QC)• A surrogate for bioequivalence studies

• FIP Guidelines for Dissolution Testing of Solid Oral Products.

• pharmacopoeias and regulatory guidelines

Dissolution ApparatusUSP I. The dosage form is placed in a cylindrical basket that is covered by a mesh.The basket is immersed in the dissolution medium and rotated at a speed of between 25 and 150

rpm. The standard beaker has a volume of 1 L, but 4 L vessels are also available. The mesh size in the basket wall can also be varied.

USP II. The dosage form moves freely in the same type of glass beaker as used for USP I. A paddle is rotated at a speed of 25 to 150 rpm. The dosage form may be placed in a steel helix in order to avoid floating.

USP III. The formulation is placed in a cylindrical glass tube with steel screens in the bottom and the top. The mesh size of the tubes may vary. This tube is moved up and down in a larger tube that contains the dissolution fluid. The amplitude of the inner tube movements is 5–40 dips/min, and the volume of the outer tube is 300 mL. Tubes containing 100 mL and 1 L are also available. The inner tube can be moved during the dissolution process between different outer tubes, which may hold different dissolution fluids.

• USP IV. The formulation is placed in a thermostated flow-cell. The dissolution fluid is pumped through the cell in a pulsating manner at a constant rate, typically between 4 and 16 mL/min. Before the inlet flow reaches the formulation, it is passed through a bed of glass pellets to create a laminar flow. A filter is placed in the cell at the outlet side of the formulation. The cell is available in different sizes/designs, and tablet holders are available as an option.

Choice of apparatus

• Correlation to in vivo data• Risk for hydrodynamic artefacts• Regulatory guidelines• Drug solubility• Need to change the dissolution medium

during dissolution testing• Ease of operation, in-house know-how and

suitability for automation

Dissolution variability• Hydrodynamics• Temperature • Chemical reactions.• USP I—clogging of basket screen, positioning of basket• USP II—adherence of formulation to the beaker wall,

floating, “entrapment” of solidmaterial in the stagnant area beneath the paddle, positioning of the paddle

• USP III—floating, adherence to tube wall or bottom screen, clogging of screens, disappearance of undissolved material through the screens

• • USP IV—clogging of filter, variations in flow rate

• Agitation Intensity:1. correlation to in vivo data,2. variability of dissolution results and3. regulatory guidelines and pharmacopoeial recommendations.• The U.S. regulatory agency recommends a stirring rate of 50–

100 rpm for USP I and 50–75 rpm for USP II.

• Dissolution test is performed with the aim to investigate the robustness of the release properties towards potential changes of the physiological conditions in vivo.

• Dissolution Test Media:• Correlation to in vivo data• Resemblance of physiological conditions in the GI tract• Regulatory and pharmacopoeial recommendations• Drug solubility and stability properties at different pH values• Known sensitivity of the formulation function for different medium

factors.• For drugs with a very low solubility in relation to the administered

dose, the above-described approaches will not provide sufficient drug solubility in the test media. In those cases, a surfactant should be added to the test medium in amounts above its critical micelle concentration (CMC) in order to solubilise the drug.

Other aspects:• 6-12 units for studies.• IR = one test point @ 80% - 85% within 30

mins to 60 mins. For poorly soluable drugs two points are required.

• ER = three test points @ max to 80 %, frequent sampling better to identify the lag phase.

• To be discussed separately:1. Bioavaibility2. IVIVC

ANIMAL STUDIES…• The possibility to perform early in vivo studies during preclinical

drug development before studies in man are possible• The use of advanced sampling techniques and other

manipulations of experimental conditions not possible in man• Studies which are cheaper and faster than studies in man.• Animal models may thus not only be used as a screening tool

before studies are performed in humans, but also for later mechanistic evaluations of findings obtained in human studies.

• Limitation of the usage of animal models is that no single species resembles all physiological properties of man.

• Models for studying absorption potential of drug: computational methods: Partial least square, principal component

analysis HTS partitioning between water and oil : log P/log D , Lipinski rule of

thumb. cell cultures : Caco – 2, IEC-18, HT-29 membrane vesicles: Brush border membrane vesicles intestinal rings or sacs, excised segments from animals in the Using chamber, in vitro and in situ intestinal perfusions, in vivo cannulated or fistulated animals and in vivo gavaged animals.

Screen ladder

Determination of Solubility

Semiquantitative determination:

Solvent(fixed volume)

Adding solute in smallincremental amounts

Vigorously shaking

Undissolvedsolute particles ?

Examinevisually

YesNo

Total amountadded upEstimated solubility

“LAW OF MASS ACTION”

Accurately Quantitative determination:

Excess drug powder150 mg/ml (15 %)+ solvent

Ampul/vial(2-5 ml)

Shaking at constant temperature (25 or 37 oC)

2 - 8 oC ?

Membrane filter0.45 mm

Determine the drugconcentration in the

filtrate

Determine the drugconcentration in the

filtrate

Determine the drugconcentration in the

filtrate

Membrane filter0.45 mm

Membrane filter0.45 mm

Sameconcentration ?

The first few ml’s of the filtrates should be discarded due to possible filter adsorption

Solubility

48 hr

72 hr

? hr

Drug

Drug breakdown

HPLCOr TLC

No

Interaction

No interaction

Excepient recommend

ed

Excepient

Alternative excepient suggested Yes

DSC50%Mixture of Drug &

excepient

Flow diagram to identify excepient compatibility with drug