Answer ALL questions. Use the answer grid provided for ALL of your answers. For each of the following questions there is ONE correct answer only.

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1 UNIVERSITY OF EAST ANGLIA School of Pharmacy Main Series UG Examination SPECIAL PAPER FOR: PHARMACEUTICAL TECHNOLOGY PHA-2FGY Time allowed: 2 hours Part ONE Answer ALL questions. Use the answer grid provided for ALL of your answers. For each of the following questions there is ONE correct answer only. Part TWO Answer THREE of the FOUR questions. Use a SEPARATE answer book for EACH question. Each question within a section has the same value. The marks distribution is shown as a percentage for each section of the question. Answer all parts of each of the individual questions you select. The mark allocation for the paper is: Part ONE carries 30% of the total mark. Part TWO carries 70% of the total mark. The following is provided: Multiple choice answer grid. Graph paper. This paper consists of 13 pages in total. Notes are not permitted in this examination. Dictionaries are not permitted in this examination. Do not turn over until you are told to do so by the Invigilator. Do not take this question paper out of the examinations room. (PHA-2FGY) Module contact: Dr Sheng Qi, PHA Copyright of the University of East Anglia Version 1

2 2 PART ONE Answer ALL questions. Use the answer grid provided for ALL of your answers. For each of the following questions there is ONE correct answer only. 1. Which of the following statements is FALSE concerning the methods of particle size determination? Coulter counters report the equivalent volume diameter of particles Photon correlation spectroscopy can only be used for particles that are smaller than about 1 nm Different particle sizing methods can give different results when the particles are not spherical Laser diffraction provides information about particle size distributions in a single measurement in the μm range Air-jet sieving tends to give more reproducible results than sieving by mechanical agitation 2. Which of the following statements is FALSE considering hoppers? A good hopper design ensures mass flow A hopper angle of about 20 ensures good flow for most pharmaceutical powders When discharging powder from a hopper, the powder flows most slowly near the walls of the hopper Bridging is a common problem with powders that flow poorly, while rat-holing occurs mainly for powders that flow well Uneven powder flow from hoppers can lead to non-reproducible doses in the final product 3. Which of the following statements is FALSE regarding particle size distributions? A bimodal distribution shows two local maxima 75% of the particles have a smaller diameter than the upper quartile The interquartile range indicates how widely the distribution is spread If the difference between the median and the lower quartile is less than the difference between the upper quartile and the median, then the distribution is negatively skewed The mean and the median of a normal distribution have the same value TURN OVER

3 3 4. Which of the following statements is TRUE regarding the chemical stability of drugs? The most common chemical routes of degradation are oxidation, reduction and photolysis Molecules with only single bonds are more susceptible to photodegradation than those that have multiple bonds Hydrolysis reactions are the slowest at low ph values, typically at ph < 3 Linear amides are less stable than -lactams The presence of chelating agents in the formulation can reduce the rate of oxidation reactions 5. Which of the following statements about the ICH/WHO guidelines for stability testing is TRUE? The United Kingdom is in Climatic Zone II Only extrapolated long-term data are required if accelerated conditions show no significant change The re-evaluation date cannot be later than 6 months after the last actual data point measured under long-term conditions The accelerated conditions for Zones I and II are 25 C/60% RH Products that are intended for storage in a fridge must be tested at a storage temperature of 0 ± 3 C 6. Which of the following statements is FALSE with respect to the temperature dependence of reaction rates? Deviation of the Arrhenius plot from a straight line can indicate a change in reaction mechanism with temperature Endothermic reactions proceed faster at higher temperatures, while exothermic reactions proceed more slowly When constructing an Arrhenius plot, the temperature should be given in Kelvin The frequency factor is related to the chance of productive collisions between the reacting atoms or molecules The activation energy can be calculated from the slope of the Arrhenius plot 7. Which of the following statements is FALSE considering drug degradation reactions? Oxidation reactions often involve free radicals The rate of photolysis reactions is influenced significantly by storage temperature The rate of hydrolysis reactions is influenced significantly by ph The stages of free radical reactions are initiation, propagation and termination Deamidation of proteins is a hydrolysis reaction

4 4 8. Which of the following statements is FALSE concerning simple compressed tablets? Tablet shape is always an issue They are suitable for formulating non-potent drugs Loose powder on surface may lead to cross-contamination of products The tablet can be compressed from either powder or granules Drug release from these tablets can be immediate, controlled or targeted 9. Which of the following statements is FALSE concerning film coated tablets? Polymers are commonly used as materials for film coating The film coat is approximately 2 to 4% (w/w) of the core tablet weight Film coating can be used to modify the drug release Core tablet shape is not important for film coating Film coats can be coloured to aid tablet identification 10. Which of the following is NOT the possible mechanism that holds the granules together with regards to granulation? Covalent forces Solid bridges from deposition of binders Solid bridges from deposition of other dissolved materials in the formulation Surface-tension type forces from residual moisture Van der Waals force between the particles 11. Which of the following is FALSE concerning the wet granulation process? Dried granules should be milled to remove large lumps Lubricant is added to milled granules immediately before tabletting Dried granules usually have a porous structure The granules should be oven dried followed by air-drying for as long as possible Undergranulation normally results in very soft tablets 12. Which of the following statements is TRUE concerning tabletting? Sticking problems may be solved by increasing the quantity of the lubricant Typical compression pressure is from 0.1 MPa to 1 MPa Temperature will remain the same during compression Tablet hardness is only determined by the compression pressure Segregation can be improved by increasing granule friability TURN OVER

5 5 13. Which of the following statements is TRUE concerning film coating? Rough surfaces can be improved by decreasing spray rate Enteric coating material is soluble in acid media HPMC shows good film strength Coating suspension concentration is usually approximately 1% The tablet bed is always heated up to 100 ºC 14. With regards to water loss from a wet solid, which of the following statements is FALSE? It is most rapid during the constant rate period It has the highest rate at the end of the process It may involve a first and second falling rate period It may take place from an effectively free water surface It may take place from within the bed itself 15. With regards to fluidised bed drying, which of the following statements is TRUE? It involves water loss from individual particles It involves application of a vacuum to cause flotation It is a slow and expensive process It involves formation of a bed that behaves like a gas It is used to obtain dry proteins from solution 16. When considering the freezing of an aqueous solution of a pharmaceutical, which of the following is FALSE? Ice crystals may be formed The concentration of the solute will increase The system may form a eutectic The system may form an amorphous dispersion The system will freeze at 0 C or 273 K 17. Which of the following statements is FALSE with respect to radioactivity? 99m-Technetium emits gamma radiation with an energy of 250 kev Beta decay can be either "positive" or "negative" 111-Indium decays to 111-Cadmium via electron capture Alpha particles consist of two neutrons and two protons After isomeric transition, the atomic number of the daughter nuclide is the same as the parent nuclide

6 6 18. Which of the following statements is FALSE in terms of wet granulation end point detection? Manual determination cannot be used on production scale The temperature rise method is suitable for a small scale The pressure detector should be placed vertically away from the chopper blade The temperature will be stabilised at the end point of the temperature rise measurement A power meter is not suitable for modern powerful mixers 19. Which of the following statements is TRUE with respect to radiopharmaceuticals? 99m-Technetium has a half-life of 2 days 99m-Technetium can be attached to a range of carriers to manipulate its biological distribution The 99m-Technetium generator is known as a "pig" Radiopharmaceuticals are subject to the normal "manufacture-test-use" protocol Radiopharmaceuticals must be autoclaved before use 20. Which of the following statements is TRUE concerning the mixing of powders? Agitator mixers rely mostly on the diffusive mechanism of mixing A longer mixing time will always lead to a more uniform mixture When testing the uniformity of a powder mixture it is best to take all samples from the bottom of the powder bed The variation in the percentage drug content of a drug / excipient mixture will appear lower if larger samples are taken for analysis Trajectory segregation leads to the accumulation of smaller particles near the edge of the powder bed 21. Which of the following statements about the chemical degradation of drugs is FALSE? Heat often can accelerate hydrolytic degradation Trace metals can often catalyse oxidation Ester hydrolysis is ph dependent Amide hydrolysis can only be base-catalysed Photolysis can be catalysed by some pharmaceutical excipients TURN OVER

7 7 22. Which of the following statements about amorphous materials is FALSE? Amorphous materials are not stable thermodynamically, but may be stable kinetically Under identical experimental conditions, the dissolution rate of an amorphous drug is higher than the dissolution rate of the same drug in a crystalline state Plastics used for pharmaceutical packaging are usually amorphous materials Amorphous materials become brittle when cooled below their glass transition temperature Amorphous materials are structurally disordered and the spatial arrangement of molecules in them is completely random 23. Which of the following statements is TRUE considering colonic delivery? Transit times in the colon are dramatically different between male and female patients Colonic delivery is useful for conditions such as Crohn s disease The harsh conditions of the colon region make it an unfavourable administration site for the systemic delivery of protein drugs The extent of proteolysis in the colon is similar to the small intestine Azo-polymers used for colon targeted delivery are soluble in neutral ph 24. Which of the following statements is FALSE concerning the process of filling powders into hard gelatin capsules? The filling uniformity of the dependent-type fillers is less dependent on the powder flow properties than the independent-type fillers A dependent-type filler uses the capsule itself as a powder measure Powder is compressed into a solid rod before it is transferred to the capsule shell in an independent-type filler The volume of the dosing tube of an independent-type filler is adjustable The process must be conducted in a low humidity environment 25. Which of the following statements is TRUE considering softgel capsules? Softgel capsules can only be mono-coloured Softgel capsules are made from high bloom gelatin Glycerol can be used as a plasticiser in softgel capsule shells Softgel capsule shells contain 20% water Softgel capsules are mostly used for controlled drug delivery

8 8 26. Which of the following statements is TRUE concerning packaging design and labelling? The batch number is not required on the packaging Legal category POM refers to pharmacy only medicine The strength of the medicine is required to be labelled on the primary packing only The labelling must follow official regulation requirements Sophisticated packaging design is encouraged for POM medicines 27. Which of the following statements is FALSE concerning tamper-proofing? Foil seals for creams can provide tamper-proofing for the product Push-through lidding of blister packs is good for tamper-proofing Seals on the secondary packaging can enhance tamper-proofing Metal strips are good for tamper-proofing Tamper-proofing is more important in POM than OTC products 28. Which of the following statements is TRUE concerning tablet specifications? Under the content uniformity specification, 20 tablets should be tested at the stage 1 test Stage 2 of the pharmacopoeial "Content Uniformity" specification allows a range of 75 to 125% around the mean value on the 20 tested tablets A batch passes the content uniformity test, if all of tablets tested have values between 85 and 115% of the mean The BP specifications for the friability test allow up to 2% tablet weight loss The same general pharmacopoeial specifications apply to all tablet and capsule products 29. Which of the following statements is FALSE concerning the polymers used for oral controlled drug delivery? Film coats made from azo-polymers are used to provide colonic targetting HPMC may be used as a matrix former for monolithic devices Eudragit S is a polymer for enteric coating and is soluble at ph 4-6. Chitosan is a polymer with mucoadhesive properties Ethylcellulose is commonly used to make drug release rate limiting membranes TURN OVER

9 9 30. When preparing hard gelatin capsule shells, which of the following statements is TRUE? The gelatine is first dissolved in cold deionised water during capsule manufacture The hard gelatin shells are made from dipping pins into a concentrated gelatin solution then followed by drying A size 3 capsule shell has approximately a 3 ml volume Titanium dioxide is often used as colourant for producing red capsules Hard gelatin capsule shells can only be used for solid powder filling END OF PART ONE

10 10 PART TWO Answer THREE of the FOUR questions. Use a SEPARATE answer book for EACH question. 31. Answer ALL parts (a) to (e). As an industrial pharmacist, you are studying the solid-state behaviour of new drugs. One drug is found to exist in two polymorphic crystalline forms. (a) Define the term polymorphism, as used in this context. [10%] (b) Discuss the importance of polymorphism to the formulation of solid oral dosage forms. [25%] (c) The two polymorphs are found to have different angle of repose and tap density values. Explain the principles behind these testing procedures, including any relevant diagrams and equations. Why are these tests commonly used during the formulation of solid oral dosage forms? [25%] (d) The two polymorphs are found to have different particle size distributions. Explain the importance of particle size and particle size distribution for the formulation of solid oral dosage forms. [20%] (e) Explain the principles of sieve analysis as a means of assessing the particle size distribution of a powder. Include in your answer a consideration of the data processing required. [20%] TURN OVER

11 Answer ALL parts (a) to (c). You are a formulation scientist developing a controlled-release tablet formulation targeted for colon drug delivery intended for once daily use. (a) Describe the rationale behind the colon-targeted drug delivery. Discuss the advantages and disadvantages. [40%] (b) Describe different formulation approaches for achieving colon-targeted drug delivery. [40%] (c) Describe an experiment that could be performed to determine the transit of controlled-release oral formulations in human volunteers. [20%]

12 Answer BOTH parts. You work in the "Formulation and Process Development" department of a pharmaceutical company and are currently developing an immediate-release soft gelatine capsule formulation of a new poorly water-soluble drug. The oral absorption data of the new soft capsules showed dramatic enhancement of absorption in comparison to the directly compressed tablet formulation. The intended capsule strength of the drug is 30 mg and the capsule weight is 500 mg. (a) Explain the possible reason for enhanced oral absorption of the drug in the soft gelatin capsule in comparison to tablet formulations. [30%] (b) During the manufacture of the capsules, the following data set on one batch of the uncoated capsules is listed in the table below. Test Capsule weight uniformity (mg) Content uniformity (mg) Disintegration time at 37 C (mins) Results 495, 498, 505, 501, 506, 494, 509, 493, 501, 503, 505, 506, 494, 498, 506, 484, 502, 509, 497, , 25.6, 28.8, 26.6, 29.7, 31.3, 30.3, 28.9, 29.6, , 19, 15, 15, 14, 22, 18, 17, 16, 12 (i) Briefly describe the BP method for measuring the weight uniformity of soft gelatine capsule products. Comment on whether the batch meets the BP specification for capsule weight uniformity. [25%] (ii) Briefly describe the BP method for measuring the content uniformity of soft gelatine capsule products. Comment on whether the batch meets the BP specification for capsule content uniformity. [25%] (iii) Briefly describe the BP method for measuring the disintegration time of soft gelatine capsule products. Comment on whether the batch meets the BP specification for capsule disintegration time. [20%] TURN OVER

13 Answer ALL parts (a) to (d). Stress-testing of the drug nitazoxanide by intensive UV irradiation gave the following results. The main route of photodegradation was identified as: Nitazoxanide The concentration of the drug in a solution preparation during irradiation was measured to be: Time / h Concentration / ( μg ml -1 ) (a) Explain the term stress testing and its role in the development of pharmaceutical formulations. [20%] (b) Determine the reaction order by plotting the appropriate linear graph. Determine the reaction rate constant (k) and the half-life of the drug from the graph. Show your working. [40%] (c) When stored in the dark, nitazoxanide solutions degrade by a different route. Give the most likely degradation reaction. [10%] (d) Suggest strategies to minimise the degradation of nitazoxanide, taking into account both its photodegradation and the reaction discussed in part (c). [30%] END OF PAPER