Devesh Bhatt ppt on Preformulation Studies

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Presentation Transcript

A SEMINAR ON PREFORMULATION STUDIES : 

A SEMINAR ON PREFORMULATION STUDIES Presented by: Devesh Bhatt DEPARTMENT OF PHARMACEUTICS NMIMS UNIVERSITY

Slide 2: 

Product Development Timeline Develop Synthetic Route First Supplies Non GLP Probes IND/Phase I/II Safety Drug Substance Transfer to Manufacturing Validation Safety Assessment Extended Safety Studies Degradate Qualification Carcinogenicity PAI Launch Quantities Product Development Preformulation Studies Biopharm Evaluation Formulation Design Phase I/IIA Formulations Analytical Methods Composition & Process Defined Probe Stability $5-10MM Process Development and Scale Up Biobatch Specifications MCSS Transfer to Manufacturing First in Man Phase IIB Approval Develop Process and Scale-up Establish Specifications Phase I/IIA Wide Dose Range Multiple Formulations Phase IIB Dose Range Phase III Final process >1/10 scale PAI Discovery Launch Validation Launch Quantities Clinical Program Phase III $250-800MM 3-10 years 4-8 years File NDA WMA crg development timeline

WHAT ARE PREFORMULATION STUDIES??? : 

WHAT ARE PREFORMULATION STUDIES??? The discovery and development of NCE’s(New chemical entities) into a stable, bioavailable, marketable drug products is a long but really a rewarding process. Those studies which are necessary to fully characterize molecules during the discovery and development process so that the NCE’s have the appropriate properties are called as preformulation studies. These studies commences when a newly synthesized drug shows sufficient pharmacologic promise in animal models to warrant evaluation in man.

NEED FOR PREFORMULATION STUDIES:- : 

NEED FOR PREFORMULATION STUDIES:- Actually NCE’s are always having a sigmoidal curve i.e. vulnerability → growth→ decline. So to avoid the decline parameter to the best possible way, these preformulation studies are done To facilitate drug property based designs To give NCE’s the highest possibility of success Understanding or the knowledge of deficiencies such as molecules weakness, decay mechanism, or the drug decomposition (aspirin undergoing ester hydrolysis) occurring during formulation process and thus can be eradicated To fulfill the goal of designing optimum drug delivery systems.

1ST - BULK CHARACTERISATION : 

1ST - BULK CHARACTERISATION 1) CRYSTALLINITY AND AMORPHISM

Slide 6: 

CRYSTALLINITY AND AMORPHISM: Habit is outer appearance of a crystal. amorphous crystalline - repeated spacing of atoms - have less energy - need lot of energy to break crystalline form - so solubility is low - randomly placed molecules - have more energy - need less energy to break molecules - so solubility is high Internal structure

2) POLYMORPHISM : 

2) POLYMORPHISM

2) POLYMORPHISM : 

2) POLYMORPHISM Ability of a compound to crystallize as more than 1 distinct crystalline species with different internal lattices. These species are polymorphs and this phenomenon is called polymorphism. Their existence can be determined by - optical crystallography - x-ray diffraction - DSC (Differential Scanning Calorimetry) - Thermal analysis E.g.- Chloramphenicol palmitate A,B,C out of which B form has the best solubility while A form is biologically inactive

Slide 9: 

POLYMORPHS Enantiotropic Monotropic - Reversible change into another by change in temperature or pressure .e.g- Sulphur - unstable at all temperature or pressure e.g.-Glyceryl stearates POLYMORPHS Stable Metastable - low energy - high m.p - low solubility - low rate of dissolution - high energy - low m.p - high solubility - high rate of dissolution Amorphous>metastable>stable

Slide 10: 

Metastable form 2 is converted into form 1 i.e stable form on addition of organic solvent aceto nitrile

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Polymorphs (single molecules) Crystalline Molecular adduct Enantiotrophic Monotropic Nonstoichiometric complexes Stoichiometric complexes (pseudopolymorph) Organic solvates Hydrates Internal structure of compound Non-crystalline (amorphous)

Slide 12: 

Launch in 1996 Summer of 1998 TransForm 2002 – 6 week effort Summer of 1998 Various crystalls with their melting points

3) HYGROSCOPICITY : 

3) HYGROSCOPICITY Tendency to absorb moisture from air. E.g.- water soluble drugs Deliquescent material( materials which become liquid by absorbing moisture from air) absorbs sufficient water from air E.g.- NaCl on humid day Thus for monitoring moisture these methods can be used: - Gravimetric test - TGA (Thermo Gravimetric Analysis) - Karl Fischer titration - G.C (Gas chromatography)

4) FINE PARTICLE CHARACTERISATION : 

4) FINE PARTICLE CHARACTERISATION

4) FINE PARTICLE CHARACTERISATION : 

4) FINE PARTICLE CHARACTERISATION Very imp. Property and here smallest particle should be tested to facilitate homogeneous sample preparation 1) Coulter Counter Technique To check particle size and particle volume

2) BET(BRUNAUER,EMMET,TELLER) NITROGEN ADSORPTION APPARATUS : 

2) BET(BRUNAUER,EMMET,TELLER) NITROGEN ADSORPTION APPARATUS Measurement of surface area

3) SEM( SCANNING ELECTRON MICROSCOPY) : 

3) SEM( SCANNING ELECTRON MICROSCOPY) to check surface morphology

5) BULK DENSITY : 

5) BULK DENSITY

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Bulk Density :- - If density problem is identified, then it must be corrected by milling, size reduction and slugging - Knowledge of absolute and bulk density of the drug substance is very useful in having some idea  as to the size of final dosage form. Carr’s index (%)          =     Tapped density – bulk density *100                                                 Tapped density -A similar index has been defined by Hausner : Hausner ratio   =          Tapped density                                    bulk density -Angle of repose:- The maximum angle which is formed b/w the surface of a pile of powder and horizontal surface is called the angle of repose.

6) POWDER FLOW PROPERTIES : 

6) POWDER FLOW PROPERTIES

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-Powders are classified into: 1) Free flowing 2) Non free flowing (cohesive powders) -If not of proper density then are densified by slugging - Free flowing powder flow analyzed by simple flow apparatus such as Grounded metal tube ---> from which drug flows through an orifice onto an electronic balance --->connected to strip chart recorder ---> several flow rates determined at each of orifices sizes.

2nd - SOLUBILITY ANALYSIS : 

2nd - SOLUBILITY ANALYSIS

1) COMMON ION EFFECTS : 

1) COMMON ION EFFECTS

Our gastric juice pH is 1-2 and the chloride ion is between 0.1 M and 0.15 M Now suppose any drug containing chloride e.g. salts of chlortetracycline containing chloride when entered in our body which is already having chloride in the gastric juice ---> then the solubility of the drug decreases.

2) pH and pka SOLUBILITY PROFILE : 

2) pH and pka SOLUBILITY PROFILE

Slide 27: 

Pka Determination: - The Henderson – Hasseslebach  equation provides an estimate of the ionized and un ionized durg concentration at a particular pH. - For acidic drugs, pH = pKa + log (ionized drug) / un-ionized drug) - For basic drugs, Ph = pka + log (unionised drug / ionised drug ) - Buffers, temperature, ionic strength and cosolvent can affect the pka value. - Potentiometric titration offers maximum sensitivity for compounds with pka values in the range of 3-10

3) SOLUBILIZATION : 

3) SOLUBILIZATION

Slide 29: 

Solubilisation is increased by co solvent addition. E.g.- propylene glycol solubilizes drug molecules by disrupting the hydrophobic interactions of water. More non polar the solute ---> greater is the solubilisation achieved by co solvent addition

Slide 30: 

lipophilic ester is solubilised to a great extent by addition of propylene glycol than by parent compound

4) THERMAL/HEAT EFFECTS : 

4) THERMAL/HEAT EFFECTS

Slide 32: 

Drugs which are unstable to heat requires refrigerative storage or lyophilisation (these products must be used within short periods) If it is endothermic ---> ∆H is +ve increase in temp ---> increase in drug solubility If it is exothermic ---> ∆H is – ve increase in temp ---> decrease in drug solubility For determining ∆H we have ln S= - ∆H /RT + C S=molar solubility ,T=temperature in Kelvin, R= gas constant

5) DISSOLUTION : 

5) DISSOLUTION

Slide 34: 

Dissolution studies can help to identify potential bioavailability problem areas. 3 theories: Diffusion layer model / film theory Danckwert’s model / penetration or surface renewal theory Interfacial barrier model / Double barrier or limited solvation theory dC/dt = DAKW/O (CS – CB)/Vh

6) Partition coefficient : 

6) Partition coefficient

Slide 36: 

Partition coefficient is defined as the ratio of un-ionised drug distributed between the organic and aqueous phases at equilibrium. PO/W = Coil/Cwater here both are in equilibrium Thus in any formulations , the lipophilic/hydrophilic balance should always be maintained to yield a perfect formulation.

3rd STABILTY ANALYSIS : 

3rd STABILTY ANALYSIS Focuses on evaluation of chemical stability during handling, formulation, Storage and administration of drug candidate.

1) STABILTY IN TOXICOLOGY FORMULATIONS : 

1) STABILTY IN TOXICOLOGY FORMULATIONS

Slide 39: 

Evaluates samples of toxicology preparations Solutions, suspensions toxic preparations are stored in flames sealed ampoules at various temperatures. Shaking is done to check dispersability ion suspensions Drug given in food of animals. Water, vitamins, minerals in the food reduce the shelf life of a drug For best stability analysis fresh sample of food is used and given.

2) SOLUTION STABILITY : 

2) SOLUTION STABILITY

Slide 41: 

Helps for understanding solubility of drugs and thus we get the base of later formulation of any drug. Determined by HPLC, U.V. spectroscopy, Fluorescence spectroscopy, GC Moreover, Reverse phase HPLC offers a accurate means for detecting solubility Sometimes filtered saturated solutions should be carefully examined using a high intensity light beam to detect presence of solid by a light microscope These studies includes the following subparts:

A) COLOUR : 

A) COLOUR

Slide 43: 

Colour is generally a function of drug inherent chemical structure relating to certain level of unsaturation Colour intensity is due to presence of chromophore such as NH2,CO,etc Under stressed conditions of light and oxygen and if degradation of product starts, then change of colour takes place and it may lead to unacceptable formulation.

B) ODOUR : 

B) ODOUR

Slide 45: 

Odour must be checked by continuous smelling of upper head space of the container If bad must be reported by the analyst some have characteristic odour like garlic smell

C) DRUG EXCIPIENTS INTERACTIONS : 

C) DRUG EXCIPIENTS INTERACTIONS

Slide 47: 

Interaction of drug excipients can occur during any unit operation i.e. during mixing, blending, drying, granulating, etc and thus resulting in change in dissolution patterns. Formulator should have thorough understanding of drug excipient interactions so that most appropriate excipient can be selected to enable formulation to perform optimally. Effect of magnesium stearate on disintegration time of tablets containing potato starch or sodium starch glycolate -formation of lubrication film -increase in disintegrating time and thus -delayed dissolution

D) EFFECT OF OXYGEN : 

D) EFFECT OF OXYGEN

Slide 49: 

Due to oxidation , - shelf life reduces - changes in color - Potency of drug becomes less So antioxidants are used to prevent oxidation e.g sodium bisulphate, sodium metabisulphate

E) LIGHT STABILITY : 

E) LIGHT STABILITY

Slide 51: 

Tests are performed by placing samples in open vials and control samples into another colured glass bottle exposed to light for 4 weeks ---> observed for stability changes if light sensitive ---> stored in amber colured glass bottles

F) MELTING POINT : 

F) MELTING POINT

Slide 53: 

Defined as temperature at which solid and liquid phase are in equilibrium To detect purity of compound Purity determined by slightly lowering or heating above M.P. where by which impurities in pure drugs are precipitated. The melting point of  a drug can be measured using three techniques such as:- 1)Capillary Melting 2)Hot Stage Microcopy 3)Differential scanning calorinetry or thermal Anaylysis.

G) MOLECULAR STRUCTURE AND WEIGHT : 

G) MOLECULAR STRUCTURE AND WEIGHT -investigator can make initial judgement regarding potential properties and functional group reactivity

H) NEW SALT FORMS : 

H) NEW SALT FORMS Solubility

3) SOLID STATE STABILITY : 

3) SOLID STATE STABILITY

Slide 57: 

Primary objective is identification of stable storage conditions for drug in solid state and identification of compatible excipients for a formulation. Solid state reactions are much slower and difficult to interpret than solution state reactions because of reduced number of molecular contacts between drug and excipients. Polymorphic changes detected by DSC and I.R. Surface discoloration detected by surface reflectance measurements HPLC Analysis also done

CONCLUSION : 

CONCLUSION Just as we learn A,B,C,D in K.G. standard and then move ahead in our life, in the very same way a drug has to pass preformulation stage and then it can go ahead and finally can get admission into the market. By comparing the physicochemical properties of each drug candidate within a therapeutic group, the preformulation scientist can assist the synthetic chemist to identify the optimum molecule, provide the biologist with suitable vehicles to elicit pharmacological response and advise the bulk chemist about the selection and production of the best salt with appropriate particle size and morphology for subsequent processing.

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