You are hereA REVIEW ARTICLE ON RESEARCH & DEVELOPMENT OF PHARMACEUTICAL MEDICINE WITH SPECIAL EMPHASIS ON PREFORMULATION (A NEED FOR DOSAGE FORM DESIGN)
A REVIEW ARTICLE ON RESEARCH & DEVELOPMENT OF PHARMACEUTICAL MEDICINE WITH SPECIAL EMPHASIS ON PREFORMULATION (A NEED FOR DOSAGE FORM DESIGN)
Melting Point :-
The melting point of a drug can be measured using three techniques :-
2)Hot Stage Microcopy
3)Differential scanning calorinetry or thermal Anaylysis.
Capillary Melting :-
Capillary melting gives information about the melting range but it is different to assign an accurate melting point.
Hot Stage Microcopy:-
This the issued observation of melting under a microscope equipped with a heated and lagged sample stage. The heating rate is controllable and upto three transitions can e registered.
Differential Scanning Calorimeltry and thermal analysis :-
Differential thermal analysis (DTA) measures the temperature difference between the sample and a reference as a function of temperature or time when heating at a constant rate differential scanning calorinetry (DSC) is similar to DTA except that the instrument measures the amount of energy required to keep the sample at the same temperature as the reference i.e. it measures the enthalpy of transition.
Crystal Properties and Polymorphism :-
Many drug substance can exit in more than one crystalline from with different space lattice arrangements. This property is known as polymorphism. Polymorphs generally have diffrent melting points, x-ray diffraction patterns and solubility even though they are chemically identical.
Differences in the dissolution rates and solubilities of different polymorphic forms of a given drug are very commonly observed. When the absorption of a drug is dissolution rate limited, a more soluble and faster-dissolving from may be utilized to improve the rate and extent of bioavailability.
For drugs pane to degradation in the solid state, physical form of the drug influences degradation. Selection of a polymorph that is chemically more stable is a solution in many cases. Different polymorph also lead to different morphology, tensile strength and density of power bed which all contribute of compression characteristics of materials. Some investigation of polymorphism and crystal habit of a drug substance as it relates to pharmaceutical processing is desirable during its Preformulation evaluation especially when the active ingredient is expected to constitute the bulk of the tablet mass. Although a drug substance may exist in two or more polymorphic forms, only one form is theromdynamically stable at a given temperature and pressure. The other forms would convert to the stable form with time. In general, the stable polymorph exhibits the highest melting point , the lowest solubility, and the maximum chemical stability. Various techniques are available for the investigation of the solid state. These include microscopy (including hot stage microcopy), infrared spectrophotometry, single-crystal x-ray and x-ray power diffraction, thermal analysis, and dilalometry.
Particle Size, Shape and Surface Area:-
Bulk flow, formulation homogeneity, and surface-area controlled processes such as dissolution and Surface morphology of the drug particles. In general, each new drug candidate should be tested during Preformulation with the smallest particle size as is practical to facilitate preparation of homogeneous samples and maximize the drug’ s surface area for interactions.
Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes. The effect is not only on the physical properties of solid drugs but also, in some instances, on their biopharmaceutical behavior. It is generally recognized that poorly soluble drugs showing a dissolution- rate limiting step in the absorption process will be more readily bio available when administered in a finely subdivided state rather than as a coarse material.
In case of tablets, size and shape influence the flow and the mixing efficiency of powders and granules. Size can also be a factor in stability: fine materials are relatively more open to attack from atmospheric oxygen, the humidity, and interacting excipients than are coarse materials.
- Determination of particle size
-Determination of surface area
Particle size Determination:-
Though microscopy is the simplest technique of estimating size ranges and shapes, it is to slow for quantitative determination the material is best observed as a suspension in non dissolving fluid. Saving is less useful technique at preformulation storage due to lack of bulk material. Andreason pipette is based on the rate difference of sedimentation of different particles, but techniques like this are seldom used due to their tedious nature instruments based on light scattering, (Royco), light blockage (HIAC) and blockage of electrical conductivity path (coulter counter) are available.
Surface Area Determination:-
Surface area is most commonly determined based on brunaver emette teller (BET) theory of adsorption. Most substances adsorb a mono molecular layer of gas under certain conditions of partial pressure of gas and temperature. Knowing the monolayer capacity of adsorbent and the area of absorbale molecule, the surface area can be calculated the adsorption process is carried out with nitrogen at-195 degree Celsius at a partial pressure attainable when nitrogen is in a 30% temperature with an inert gas (helium). The adsorption takes place by virtue of vander wall’s forces.
Power Flow Properties:-
When limited amounts of drugs are available Power flow properties can be evaluated by measurements of bulk density and angle of repose. Changes in particles size, and shape are generally very important an increase in crystal size or a more uniform shape will lead to a small angle or rpose and a smaller Carr’s index.
Bulk Density :
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 the density of solids also of affects their flow Properties Carr’s compressibility index can be used to predict the flow properties based on density measurement.
Carr’s index (%) = Tapped density – Pored density *100
A similar index has been defined by Hausner :
Hausner ratio = Tapped 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.
Relationship between flow, angle of repose, Carr’s index fee power flow
Angle of repose
Carr’s index ( % )
Fair to passable
Chemical stability profile:
Preformulation stability studies are usually the first quantitative assessment of chemical stability of a new drug. These studies include both solution and solid state experiments under condition typical for the handing, formulation, storage, and administration of a drug candidate as well as stability in presence of other recipients.
Factor effecting chemical stability critical in rational dosage form design include temperature, pH and dosage form diluents. The method of sterilization of potential product will be largely dependent on the temperature stability of the drug. Drugs having decreased stability at elevated temperatures cannot be sterilized by autoclaving but must be sterilized by another means, e.g., filtration. The effect of pH on drug stability is important in the development of both oral administration must be protected from the highly acidic environment of the stomach. Buffer selection for potential dosage forms will be largely based on the stability characteristic of the drug.
- Solid state stability
- Solution phase stability
- Compatibility studies : stability in the Presence of excipients
- Typical stability protocol for anew Chemical Entity
Solid state stability:-
Chemical instability normally results from either of the following reaction :- hydrolysis, oxidation, photolysis and pyrolysis, Chemical structure of the drug is the determination of drug to either of these attacks. Esters and lactase and to lesser extent, amides are to prone to solvolysis . Instauration or electron rich centre in the structure make the molecule vulnerable for free radical mediated or photo-catalysed oxidation. physical properties of drugs. Amorphous materials are less stable than their crystalline forms. Denser materials are more stable to ambient stress.
Elevated temperature studies:-
The elevated temperatures commonly used are 40, 50, and 60 degree centigrade with ambient humidity. The samples stored at highest temperature are observed weekly for physical and chemical changes and compared to an appropriate control . If a substantial change is seen, samples stored at lower temperature are examined . If no changesisseen after 30 days at 60 degree centigrade, the stability prognosis is excellent .
Stability under high humidity conditions :-
Solid drug samples can be exposed to different relative humidity conditions by keeping them in laboratory desiccators containing saturated solutions of various salts. The closed desiccators in turn are kept in oven to provide constant temperature. The preformulation data of this nature are useful in determining if the material should be protected and stored in controlled low humidity environment or if non aqueous solvent be used during formulation.
Photolytic stability :-
Many drugs fade or dorpen on exposure light. Though the extent of degradations small and limited to the exposed surface area, it presentsanaesthetic problem. Exposure of drug 400 and 900 foot-candles of illumination for 4 and 2 week periods respectively is adequate to provide some idea of photosensitivity. Resulting data may be useful in determining if an amber colored container is required or if color masking bye should be used in the formulation .
Stability to Oxidation :-
Drug’s sensitivity to oxidation can be examined by exposing it to atmosphere of high oxygen tension. Usually a 40% oxygen atmosphere allows for rapid evaluation. A shallow layer of drug exposed to a sufficient headspace volume ensures that the system is not oxygen limited. Samples are kept in desiccators equipped with three-way stop cocks, which are alternatively evacuated and flooded with desired atmosphere. The process is repeated 3 or 4 times to ensure 100% desired atmosphere. Results may be useful in predicting if an antioxidant is required in the formulation or if the final product should be packaged under inert atmospheric conditions.
Compatibility studies :-
The knowledge of drug excipients interaction is useful for the formulation to select appropriate excipients. The described preformulation screening of drug excipients interaction requires only 5mg of drug in a 50% mixture with the excipients to maximize the likelihood of obscuring an interaction . Mixtures should be examined under nitrogen to ultimate oxidation and paralytic effect at a standard heating rate on DSC, over a temperature range, which will encompass any thermal changes due to both the drug and appearance or disappearance one or more peaks in themogrames of drug excipient mixtures are considered of indication of interaction.
Solution phase stability:
As compared with the dry form, the degradation is much rapid in solution form. It is important ascertain that the drug doesn’t degrade when exposed to GI fluid. The pH based stability study, using different stimulator GI condition can be designed. A poor solution stability of drug may urge the formulator to choose a less soluble salt form, provided the bioavailability is not compromised
It is essential to test the in vivo behavior of the new drug for successful formulation of a dosage from good bioavailability. Partial in vivo and in vitro test are designed to study pharmacokinetic profile of the drug.
Preformulation studies have a significant part to play in anticipating formulation problems and identifying logical path in both liquid and solid dosage form technology. The need for adequate drug solubility cannot be overemphasized. The most appropriate salt for development. Stability studies in solution will indicate the feasibility of parental or other liquid dosage form and can identify methods of stabilization. In parallel solid-state stability by DSC, TLC and HPLC in the presence of tablet and capsule excipient will indicate the most acceptable vehicles for solid dosage form.
By comparing the physicochemical properties of each drug candidate with in 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.
GENERAL INSTRUMENTAL REQUIREMENTS OF D4:-
For research methods and labs-
Double beam uv-visiblespectroscopy
NMR (1Hnmr, 13Cnmr) spectroscopy
Chromatography (liquid chromatography/hplc, GC, hptlc, TLC, paper chromatography, column chromatography)
X-rays crystallography, muffle furnace, refractometry, uv-chamber, potentiometer
Dissolution test apparatus
Karlfischer auto titrator
Bulk density apparatus
MP & BP apparatus
Hot plate with magnetic stirrer
0.1mg electronic balance
Microbiological labs setup
Stability testing labs
Animal Testing-Depends upon models and drug selections
Tablet-rapid mixer granulator, fluid bed drier, tablet punching machine 16/27/35 stations,multimill,stiffer s.s.s,stifer sieve 30 inch 12/16/20/40/60,multimill sieve size 10mm/3mm/2mm/1mm/15mm,octagonal blender ,coating psn,colloid mill, tablet dedusting machine, dies & punches, dust extracting unit,dehumidifier,starch paste castele,pressure vessel with gauge with hydrodynamic atomizing spray gun with stand & clamp, polishing pan for coating pan, tablet inspection tablet c belt and packing machine(blister/strip/alu-alu packs)
Capsule & dry syrup-s.s. Sifter, double cone blender(different capacity),semi/-automatic cap fill machine, capsule polishing and inspection machine, tray drier 24/48,aunger filling machine,p.p.cap sealing machine, labeling/printing machine,dehumidifier,capsules filling machine, capsule loader with change plates for0,1,2
Liquid oral section- sugar preparation tank .s.s jacket, tank s.s.1000/500/300/100/50lts,filter press with pump, automatic liquid bottle washing, filling/sealing/printing /gumming machine, s.s.stirer with stand, s.s.emulsifier with stand, S.S. Transfer gear pump
1. H. Brittain, Physical Characterization of Pharmaceutical Solids, Marcel Dekker, Inc., 1995.
2. H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, Inc., 1999.
3. S.R. Byrn, R.R. Pfeiffer and J.G. Stowell, Solid State Chemistry of Drugs, Second Edition, SSCI, Inc.,1999.
4. E.F. Fiese and T.A. Hagen, “Preformulation”, Chapter 8 in the Theory and Practice of Industrial Pharmacy, Lea & Febiger, Philadelphia, 1986.
5. M. Gibson, Pharmaceutical Preformulation and Formulation, HIS Health Group, Englewood, CO, 2001.
6. L.J. Ravin and G.W. Radebaugh, “Preformulation”, Chapter 75 in Remington’s Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pennsylvania, 1990.
7. W.Q. Tong, “Preformulation Aspects of Insoluble Compounds” in Water Insoluble Drug Formulation, Edited by R. Liu, Interpharm Press, 2000.
8. J. Wells, Pharmaceutical Preformulation, Ellis Horwood Limited, 1988.
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