Knowledge Centre



PREFORMULATION

For every formulation development of a product, a scientist has to perform a minimum number of preformulation studies.

Solubility study
  • Solubility of an API plays an important role in formulation development as its solubility affects the disintegration time and dissolution rate of a drug product in-vitro and in-vivo which in turn affects its bioavailability.
  • The formulation development becomes more challenging when the drug belongs to class 2 or class 4 categories of BCS classification.
  • The solubility of a drug is determined by dissolving the highest unit dose of the drug in 250 ml. of buffer adjusted between pH 1.0 and 8.0. A drug substance is considered highly soluble when the dose/solubility volume of solution are less than or equal to 250 ml. (Reference: CDER Guidance for Industry)
  • Another way of analyzing solubility is saturation solubility method. A Known excess amount of drug is added to the fixed volume of buffer ranging from pH 1.2 to pH 8.0 till the turbidity is observed. The solution is analyzed for the amount of drug dissolved per ml.
  • The most frequently adopted method to enhance the solubility of the drug is increasing the surface area by reducing the particle size of an API.

Particle size analysis
  • Particle size of an API can be obtained by sieve analysis and laser diffraction technique. Particle size of an API has to be same throughout the formulation as change in particle size may affect the reproducibility of the formulation.
  • Particle size is especially important for low soluble drugs as increase in particle size may decrease the solubility of an API.
  • Every time an API purchased either from the same vendor or from different vendor, its particle size should be same throughout the formulation.
  • Also it is advisable to cross verify the particle size internally in your own lab for the first few lots of API.
  • Finalized particle size has to be included in the in-house API specification and the API vendor should be informed about the requirement of particle size for the future supply of API.

Compatibility study

Compatibility study is done initially to find out the stability of a drug with different excipients which are likely to be used in formulation development. The compatibility study should even include ingredients such as coating agents, solvents, colors, flavors too.

  • At least three excipients of same functional property to be chosen such as three diluents, three binders, three lubricants, three coating materials etc. to save time, cost, energy and effort.
  • If different brand of excipient is used in later stage of formulation development and finalized in prototype formulation development then compatibility study of that brand of excipient has to be done with an API.
  • The ratio of drug and excipients for the compatibility study should be chosen based on percentage of drug and excipients in the unit dose.
  • Normally 10 ml of fresh transparent glass vials with plastic caps are used for compatibility study. If a product is light sensitive, use ambered colored vials.
  • The minimum information on the label is required to be put such as name of the product, experiment number, name of an API and excipients with their ratios, date of loading and date of withdrawal of the sample from the stability chamber and signature of the scientist.
  • Load the samples the same day it is prepared. So plan the compatibility study in the morning itself.
  • Generally the samples are loaded in 40 ̊ C/75% RH for 1 month and sampling is done at 15 days and 30 days.
  • At the end of the exposed period the samples are given for analysis with freshly prepared duplicate sets of all the samples having same ratio of drug and excipients.
  • Based on the analytical results the combination of drug with excipients with more impurity level can be avoided in the formulation.

Contact us to get specific suggestions on compatibility study for your product.


Photostability study of a drug substance

Photostability study is done on the drug substances which degrade in presence of light. Studies should identify precautionary measures needed in manufacturing of drug substance or in formulation of the drug product. If an API is found to be light sensitive, formulation development should be done under sodium vapor lamp and packed in light protective packing.


Light source

Sample should be exposed to both the cool white fluorescent and near ultraviolet lamp.

  • A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977(1993) and
  • A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350 nm and 370 nm; a significant proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm.

Samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours.
(Reference: Q1B- ICH guidelines)


Temperature

The formulator should maintain an appropriate control of temperature to minimize the effect of localized temperature changes.
(Reference: Q1B- ICH guidelines)


Selecting the locations for samples in photostability chamber
  • Lux meter can be used to read the intensity of a light at a particular location in the photostability chamber.
  • Insert the probe of lux meter through the hole provided in the chamber, keep it on any location on the tray and close the hole with the cap.
  • Switch on the white fluorescent and UV lamps. Check the reading on the lux meter.
  • Note the reading on the sticker label. Switch off the lamps, open the chamber and stick the label at the probe point.
  • Remove the probe, keep it on different location on the tray in the chamber and repeat the above procedure.
  • Make sure that the chosen locations have nearly similar intensity to minimize the variations in exposure of the light to test and control samples. With nearly similar intensity of light, test and control samples can be analyzed on the same day.
  • Three samples are required to be prepared for drug substance.

Weighed quantity of drug substance in

  • Open Petridish (Test sample),
  • Closed Petridish (Test sample),
  • Closed petridish covered with black polybag (control sample)

Calculating duration of light exposure to the samples

Let us assume that the intensity at a particular location in the chamber for test sample is 4430 lux. Choose another location having light intensity of nearly similar range for control sample (for example 4500 lux).

For the test sample to get exposed to 1.2 million lux hr, it has to be kept in photostability chamber for the following number of days

4430 lux x Y = 1.2 x 10 6 lux hr
Y = 1.2 x 10 6 lux hr / 4430 lux = 270.88 hr = 271 hr

Converting hours into number of days = 271 hr/24 hr = 11.29 days ~ 11.5 days

Similarly, for the control sample to get exposed to 1.2 million lux hr, it has to be kept in photostability chamber for the following number of days

4500 lux x Y = 1.2 x 10 6 lux hr
Y = 1.2 x 10 6 lux hr / 4500 Lux = 266.66 hr = 267 hr

Converting hours into number of days = 267 hr/24 hr = 11.12 days ~ 11.5 days

(Where as Y is the total hours of light exposure required)

From above example both test and control samples having exposed to nearly similar light intensity can be analyzed on the same day.


Presentation of sample
  • As a direct challenge for samples of solid drug substances, an appropriate amount of sample should be taken and placed in a petridish and protected with a suitable transparent cover if considered necessary.
  • Drug substances should be spread across the container to give a thickness of typically not more than 3 millimeters.
  • Possible interactions between the samples and any material used for containers or for general protection of the sample should also be considered and eliminated wherever not relevant to the test being carried out.
  • If direct exposure is not practical (e.g., due to oxidation of a product), the sample should be placed in a suitable protective inert transparent container (e.g., quartz).
    (Reference :Q1B- ICH guidelines)

Analysis of Samples
  • At the end of the exposure period, the samples should be examined for any changes in physical properties (e.g., appearance, clarity, or color of solution) and for assay and degradants.
  • The analysis of the exposed sample should be performed concomitantly with that of protected samples used as dark controls.
    (Reference –Q1B ICH guidelines)
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