1. Quality Control of Semisolid Dosage Forms

2. Semisolid dosage forms: Semisolid dosage forms are products of semisolid consistency and applied to skin or mucous membranes for therapeutic or protective action or cosmetic function. CREAMS: Creams are semisolid emulsion systems with opaque appearance compared with the translucent ointments. Consistency and rheological characters depend on whether the cream is w/o or o/w. O/W creams are elegant drug delivery system, pleasing in both appearance and feel after application. O/W creams are non greasy and easily washable.

3. OINTMENTS: Ointments are soft hydrocarbon (e.g. petrolatum) based semisolid preparations. Since they are mostly of greasy nature, stain cloths, and are generally poor solvent for many drugs, and usually decrease the drug delivery capabilities of the system. GELS: Organic macromolecules uniformly distributed throughout a liquid in such a manner that there is no apparent boundaries exist between the dispersed macromolecules and the liquid.

4. Ideal Properties of Semisolid Dosage Forms: 1.PHYSICAL PROPERTIES: a) Smooth texture b) Elegant in appearance c) Non dehydrating d) Non gritty e) Non greasy and non staining f) Non hygroscopic 2. PHYSIOLOGICAL PROPERTIES: a) Non irritating b) Do not alter membrane / skin functioning c) Miscible with skin secretion d) Have low sensitization effect 3.APPLICATION PROPERTIES: a) Easily applicable with efficient drug release b) Easily washable with water

5.  In quality control of products, the procedures and acceptable criteria for testing asses drug product quality attributes and product performance.  Product quality attributes: –Description - Identification –Assay (strength) - Impurities –Physicochemical properties - Uniformity of dosage –Water content - pH –apparent viscosity - microbial limits –antioxidant content - Spreadability –antimicrobial preservative content –sterility (if applicable), and other product specific tests  Product performance testing: –drug release and other attributes that affects drug release from finished products.

6.  Product quality tests for topically applied drug products:  Description: –Content or label claim of article. –Final acceptable appearance of the finished dosage form and packaging. –Identify change in color, separation, crystallization.  Identification: –Identification test should establish the identity of drug and discriminate between compounds of closely related structures, that are likely to be present. – Test should be specific for drug substance eg infrared spectroscopy, FTIR, or Raman spectroscopic methods. –Identification solely by a single chromatographic retention time may not be specific, it should be supported with additional test.

7.  Assay: –A specific stability indicating assay should be used to determine strength of the product. –In case if nonspecific method is justified, other supporting analytical procedure should be used to achieve over all specificity. Stock solution is prepared and aliquots of different concentration were prepared by suitable dilutions and their absorbance is measured and the drug content was calculated using the equation, which was obtained by linear regression analysis of calibration curve

8.  Impurities: –Process impurities –Synthetic by-products –Residual solvents –Heavy metals and other inorganic or organic impurities. –Degradation impurities should also be assessed and controlled.

9.  Specific Tests: Specific tests are considered case by case basis.  Water content: Water activity test is generally formulation dependent, low water activity reduces susceptibility to microbes.  Microbial Limits: Microbiological examination of non-sterile products. Test for specific microorganism unless the formulation itself have antimicrobial properties.  Antimicrobial preservative content: Levels of antimicrobial preservative necessary to maintain the product’s microbiological quality at all stages through its proposed usages and shelf life.

10.  Antioxidant Content: Acceptance criteria, level of antioxidant necessary to maintain product’s stability at all stages through its proposed usage and shelf life.  Sterility test: Sterility of ophthalmic preparations, and preparations applied to open wounds or burned areas should be tested.  pH: pH of topically applied products should be tested at the time of batch release and at designated stability time. One gram of the topical preparation is dissolved in 100 ml of distilled water and stored for 2 hrs. pH measurement is done in triplicate and average values are calculated. pH of semisolid dosage forms can be measured directly by using surface pH meter. N.B. For ointments it is difficult to check the pH because they are oily.

11.  Particle size: Topical products should be examined for evidence of particle size alteration (change in size, shape, form, habit, or aggregation) of active drugs at the time of batch release and at designated stability time.  Viscosity study: Viscosity of a liquid/semisolid is the measure of resistance to flow. The apparent viscosity should be tested at the time of batch release and initially at designated stability test time point. Viscosity test is formulation/ process dependent. Therefore it is not included in compendial drug product monograph, but is part of manufacturer’s specifications.

12. The viscosity of topical preparation can be measured by using Brookfield viscometer, cone-plate viscometer, and cup & bob viscometer. Brookfield viscometer: The preparations are rotated at different speeds and shear rates. At each speed the corresponding dial reading is noted.

13. Cone Plate Viscometer: For Plastic (non-Newtonian) compositions. U = C. T - T f / v f = C f. T f U = viscosity T f = torque at shearing stress axis C f = instrumental constant f = yield value

14. Uniformity of containers: Semisolid products may show physical separation during manufacturing process and shelf life. To ensure the integrity of drug product, it is essential to evaluate the uniformity of the finished product at the time of batch release and through its shelf life.  Products packaged in tubes: Carefully cut off and open the side well of tube from bottom to the top in two flaps. Inspect the exposed product visually for presence of phase separation, change in physical appearance, texture, and other properties described in the product test for description.

15.  For multiple dose products that contain ≥ 5 g quantity: Procedure 1: Using single tube, remove samples from top, middle and bottom of the tube and analyze drug substance quantitatively. Evaluate the results using Acceptance criteria A. If product fails, test three additional tubes from same batch and evaluate all test results using Acceptance criteria B. Procedure 2: Using two tubes, remove samples from top, middle and bottom of the tube and analyze drug substance quantitatively, evaluate the results using Acceptance criteria A. If product fails, test two additional tubes from same batch and evaluate all test results using Acceptance criteria B.

16.  For multiple dose products that contain < 5 g quantity: Test the top and bottom portion of tubes using procedure 1 or procedure 2. If product fails Acceptance criteria A, test two additional tubes from same batch, and evaluate all eight test results using Acceptance criteria B. Acceptance criteria A: All results are within product assay range and RSD is NMT 6%, or as specified in specifications or in compendial monograph. If RSD is ˃ 6%, use Acceptance criteria B. Acceptance criteria B: All results are within product assay range and RSD of the 1, 2 (both) assay is NMT 6% or as specified in product specifications or in compendial monograph.

17.  Products packaged in containers other than tubes: Sampling from top, middle and bottom of the jar by using a syringe. Test the samples according to the instruction outlined in products packaged in tubes.

18. Minimum fill: It is the determination of the net weight of the contents of filled containers to ensure proper contents compared to the labeled amount. Select a sample of 10 filled containers, and remove any labeling that might be altered in weight during the removal of the container contents. Thoroughly cleanse and dry the outside of the containers by a suitable means, and weigh individually. Quantitatively remove the contents from each container, cutting the latter open and washing with a suitable solvent, if necessary, taking care to retain the closure and other parts of each container. Dry, and again weigh each empty container together with its corresponding parts. The difference between the two weight is the net weight of the contents of the container.

19. The average net content of 10 containers is not less than the labeled amount, and the net content of single container is not less than 90% of the labeled amount where the labeled amount 60 g or less. Not less than 95% of the labeled amount where the labeled amount is more than 60 g but not more than 150 g.

20. Spreadability: It is the term expressed to denote the extent of area to which the preparation readily spreads on application to skin or affected area. The therapeutic efficiency of the formulation also depends upon its spreading value. Hence, determination of spreadability is very important in evaluating topical application characteristics. For determination of spreadability, single dose of preparation is applied in between two glass slides and compressed to uniform thickness by placing weight load for certain time. Thereafter the top plate was subjected to pull with the help of string attached to the hook. The time in which the upper glass slide moves the lower plate to cover a distance of 10 cm is noted. Lesser the time taken for separation of two slides better the spreadability

21. In vitro release test: This test is done to ensure within lot and lot-to-lot uniformity. In vitro release tests include diffusion cell studies to determine the drugs release profile from the semisolid product. This test is carried out in Franz diffusion cell for studying dissolution release through a cellophane membrane. Certain weight of the preparation for example 0.5 g is taken in cellophane membrane and the diffusion studies were carried at 37±1 degree, using 250 ml of phosphate buffer pH 7.4 as dissolution medium. Samples are withdrawn periodically and the samples analyzed for drug content.

22. Packaging, storage, and labeling: Ointments and other semisolid preparations are packaged either in large-mouth ointment jars or in metal or plastic tubes. Semisolid preparations must be stored in well-closed containers to protect against contamination and in a cool place to protect against product separation in heat. When required, light-sensitive preparations are packaged in opaque or light-resistant containers. The USP directs that the labeling for certain ointments and creams include the type of base used (e.g., water soluble or water insoluble).

23.  Stability Considerations: Primary indications of instability in creams/ ointments are either discoloration or odor or a noticeable change in consistency.  Instability indications of creams: –Emulsion breakage (cracking of cream) –Crystal growth –Shrinking due to evaporation of water –Gross microbial contamination.  Instability indications of ointments: –Change in consistency and excessive “bleeding” (i.e., separation of excessive amounts of liquid) –Formation of granules, or grittiness.