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The overall objective of preformulation testing is to generate information useful to the formulator in developing stable and bioavailable dosage forms which can be mass-produced.25
Scope: A detailed understanding of the properties of the drug substance is essential to minimize formulation problems in later stages of drug development, reduce drug development costs, and decrease the product's time to market (i.e., from drug substance to drug product). However, prior to reviewing the various requirements that determine the scope of preformulation studies, it is important to review how the drug discovery models are rapidly changing and why there is a need for not just one, but several levels of preformulation studies.
The first step in preformulation is to establish a simple analytical method. Most drugs absorb light in the ultraviolet wavelengths (190-390 run) as they are generally aromatic and contain double bonds. Using the UV spectrum of the drug, it is possible to choose an analytical wavelength (often Amax) suitable to quantify the amount of drug in a particular solution.4
A. UV Spectroscopy (Determination of Î»max):
Stock solution (1000 Î¼g/ml) of Drug X was prepared in Phosphate buffer pH 6.8 with 1% SLS. This solution was appropriately diluted with Phosphate buffer pH 6.8 with 1% SLS to obtain a concentration of 100 Î¼g/ml. The solution was kept in a fused silica cuvette 10 mm. The UV spectrum was recorded in the range of 200-400 nm on Shimadzu double beam UV-visible spectrophotometer at 1 cm, slit width. Wavelength of maximum absorption (Î»max) is shown in Table 53 and in fig. 16 and 17
B. Preparation of standard curve (Calibration curve) of drug X:
A standard curve was prepared by dissolving 10 mg of drug X in 100ml of Phosphate buffer pH 6.8 with 1% SLS. It was further diluted with dissolution medium i.e. Phosphate buffer pH 6.8 with 1% SLS to get solutions in concentration range of 2 to 12 Î¼g/ml. The absorbance of the solution was determined spectrophotometrically at 304 nm.
C. IR spectrum interpretation:
The infrared absorption spectrum of Drug X was obtained in a KBr disc using a Perkinâ€Elmer infrared spectrophotometer. The infrared spectrum of Drug X is shown in Fig.18 respectively. The infrared absorption bands assignments for Drug X is shown in Table 54 respectively.
3. SOLUBITY STUDY:
The solubility study for Drug X was performed by in acetic acid, water, chloroform, methanol, ethanol, MDC, acetone and ether and it is also reported in table 51.
4. Melting Point
"The melting point of a solid is the temperature at which the vapor pressure of the solid and the liquid are equal" i.e. "Temperature at which the material changes from a solid to a liquid state".
Rationale for melting point study: A pure substance melts at a precisely defined temperature, characteristic of every crystalline substance and dependent only on pressure (though the pressure dependency is generally considered insignificant). Determining the MP is a simple and fast method used in many diverse areas of chemistry to obtain a first impression of the purity of a substance. This is because even small quantities of impurities change the melting point, or at least clearly enlarge its melting range. The test is still an important technique for gauging purity of organic and pharmaceutical compounds.
Types of melting point apparatus: Four types of melting point apparatuses are:
Gallenkamp (Electronic) melting point apparatus and
automatic melting point apparatus
Observations: The melting point of Drug X was determined using Bellstone Precision Melting Point Apparatus and was reported.
7. POWDER FLOW PROPERTIES: 21,28,29
Compressibility Index (CI)
Angle of Repose
Loss on Drying
Bulk density: Density is defined as weight per unit volume. Bulk density, is defined as the mass of the powder divided by the bulk volume and is expressed as gm/ cm3. The bulk density of a powder primarily depends on particle size distribution, 'particle shape and the tendency of particles to adhere together. There are two types of bulk density. The particles are pack in such a way so as to leave large gaps between their surfaces 'resulting up in light powder of low bulk density. Here the smaller particles shift between the large particles resulting in heavy powder of high bulk density. Bulk density is very important in the size of containers needed for handling, shipping, and storage of raw material and blend. It is also important to choose the size of blending equipment.
Bulk density = Mass of the powder
It is determined by USP Bulk density Tapped density apparatus.
Tapped density: It is defined as the ratio of mass of the powder taken to the volume occupied after specified tapping (500ï‚® 750 ï‚®1250).
Tapped density = Mass of powder
It is determined by USP Bulk density Tapped density apparatus.
Compressibility index (C.I): The compressibility index has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture content, and cohesiveness of materials because all of these can influence the observed compressibility index.
CI =Tapped density - Bulk density x 100
Hausner's ratio:The hausner's ratio has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture content, and cohesiveness of materials because all of these can influence the observed hausner's ratio.
HR = Tapped density
Very Very Poor
Table 5: Limits for compressibility index & Hausner's ratio 30
Angle of repose: The angle of repose has been used to characterize the flow properties of solids. Angle of repose is a characteristic related to interparticulate friction or resistance to movement between particles. It is defined as, the maximum angle possible between the surface of the pile of the powder and the horizontal plane. If more powder is added to the pile, it slides down the sides of the pile until the mutual friction of the particles producing a surface angle (Î¸) and it is in equilibrium with the gravitational force. The angle of repose was determined by the funnel method suggested by Newman. Angle of repose is determined by the following formula:
Î¸ = tan-1 (h/r)
h-----height of cone.
r-----radius of cone.
Î¸ -----angle of repose
Angle of repose
Very Very Poor
Table 6: Limits for angle of repose 30
Loss on drying: 31
LOD is also an important property of blend because it influences the compaction and flow property, therefore hardness and disintegration has been also affected. Around 1g of blend examined in apparatus at temperature 60°c, 80°c, 105°c etc. (depends on API melting point). Generally it should be <5%.
Procedure: This was determined by weighing 1g. of sample in LOD apparatus Sartorius-MA45 at 80Â°C.
Flow properties of drug X reported in table 52 and flow properties of blend reported in table 59.
8. DRUG -EXCIPIENT COMPATIBILITY STUDY: 31
A. Plan for visual observation study:
Based on the literature study, composition of API & Excipients in terms of w/w of the target wt. of tablet may be varied. Weight of API quantity + excipient quantity will be in the range of 100-500mg for compatibility study.
API<5% w/w of
of Target wt.
API>50% w/w of
Table 7: Proportionality of Drug X and excipient for visual compatibility study
Charge the sealed vials to recommended storage conditions:
Table 8: Recommended storage conditions to charge vials for compatibility study
Initial & then 7th & 15th Day.
Table 9: Frequency of evaluation
Physical observation: (Visual)
Any sample showing above physical observation on 55Â°C as well as lower temperatures, the sample combination will be not taken for further study.