UNIVERSITY OF HERTFORDSHIRE

SCHOOL OF PHARMACY

M.PHARM., LEVEL 3: PHARMACEUTICAL ANALYSIS, PRODUCTION & QUALITY CONTROL Semester B, 2013

PHARMACEUTICS LABORATORIES: SOLID DOSAGE FORM MANUFACTURE AND EVALUATION

University of Hertfordshire School of Pharmacy Pharmaceutical Analysis, Production & Quality Control

This booklet contains information regarding the practicals in Pharmaceutical Analysis, Production and Quality Control. It outlines the methods that you will use in the practical sessions this year. In doing so, it contains a detailed description of the manufacturing process, and an outline of the evaluation laboratory session. Further details on the latter can be found in lecture notes on the PAPQC website on StudyNet and the British Pharmacopeia. Please ensure that you are familiar with the School of Pharmacy policies for working in laboratories. If you require clarification on our policies for working in a laboratory then please ask the module lead.

Lecture Notes The lecture course in this module significantly supports the practical sessions. Please ensure that you bring them with you to the laboratory session, as they will help you plan and organise your work.

Batch Record Sheets and Log Books These will be available via the PAPQC site on StudyNet. Please PRINT BRS and bring them with you to the laboratory session. You are also required to keep a laboratory book during these lab sessions, which can be inspected by staff during practicals. You will need to submit the BRS and test results from the evaluation lab at the end of the lab sessions and these will provide a valuable aid when writing up your report.

University of Hertfordshire School of Pharmacy Pharmaceutical Analysis, Production & Quality Control

COLLUSION AND PLAGIARISM

Plagiarism is a serious breach of academic conduct and will be dealt with according to the university regulations. Coursework should always be your OWN work.. All work done by other people should be acknowledged and you should ensure that you use the faculty referencing guidelines on how to reference other peoples work in your written essays and reports. You must be aware that the University takes collusion, plagiarism and cheating very seriously and you will be severely penalised for any of these offences. Brief descriptions of collusion and plagiarism, and advice on how to avoid committing such a breach of the regulations are given below. However, full details may be found in via your Student Handbook. Collusion Collusion is working together to produce assessed work in circumstances where this is forbidden. The University Regulations define collusion as the representation by an individual of work which he or she has undertaken jointly with another person as having been undertaken independently of that person. You will always be encouraged to discuss the results you have generated in practicals with the people you worked with but you should always write up your reports and laboratory logbook on your own using your own graphs and tables. Plagiarism Plagiarism is a form of academic dishonesty. The University regulations define plagiarism as the representation by an individual, whether intentionally or otherwise, of another persons work as their own or use of another persons work without acknowledgement . If you follow the guidelines given in Appendix 9 you will avoid plagiarism. There are severe penalties for plagiarism. Key aspects are summarised below: All the work in your report must be carried out by you and all the results given in your report must have been obtained by you except where you give due acknowledgement to others; All the written work (prose or text) must be written by you in your own words, except where you give due acknowledgement to others and use quotation marks, and except also for occasional brief phrases of no special significance which may be taken from other peoples work without such acknowledgement and use of quotation marks; If when you acknowledge the source of a piece of information, you must always rewrite the information in your own words which conveys your understanding of the information; All the figures and diagrams in your report must be devised and produced by you, except where you give due acknowledgement to others.

In scientific writing any reader should be able to follow an audit trail to the source of the information. The reader needs to be able to verify the truth of what is being stated. Plagiarism is academic misconduct. Students should note that it is a requirement of all Schools of Pharmacy to report all cases of academic misconduct to the Royal Pharmaceutical Society of Great Britain.

University of Hertfordshire School of Pharmacy Pharmaceutical Analysis, Production & Quality Control

LABORATORY RULES FOR PHARMACEUTICAL ANALYSIS, PRODUCTION & QUALITY CONTROL

The Health and Safety of students and staff is of paramount importance in all laboratories. The rules listed below must be adhered to at all times in laboratories, and any breach of these rules, particularly where this may cause harm to yourself or to others, will be treated as a serious disciplinary matter.

GENERAL LABORATORY RULES

Laboratory classes begin punctually as specified in your timetables. It is your responsibility to attend these classes on time. Latecomers will not be admitted and alternative classes will not be provided for latecomers, unless a satisfactory explanation of lateness is provided. This is particularly important in this module, as all the laboratory practicals are group exercises. As a minimum requirement, clean white laboratory coats must be worn at all times. Failure to do so is a breach of Health and Safety regulations, and will mean that you are excluded from the laboratory. In addition, you may be required to wear additional specific clothing depending upon the nature of the work being carried out. No smoking, eating, drinking or chewing gum is permitted in the laboratories. Mobile telephones must be switched off in laboratories. Please ensure that your mobile telephone is switched off (not on silent) during laboratory classes. You will be excluded from laboratories and awarded a mark of zero for that particular practical if you fail to adhere to this rule. Safety spectacles and masks must be worn at all times when dangerous chemicals or reagents are employed. You will be notified of such requirements as appropriate at the start of laboratory classes. Failure to comply with repeated instructions to wear safety masks will result in exclusion from the laboratory. Again, you may be required to wear additional laboratory clothing depending on the nature of specific practicals. Accidents or breakages should be reported to a member of staff immediately. Instrument failure should be reported to a member of staff immediately. All equipment to be used by others must be cleaned immediately after use. Experiments are not considered to be completed until you have cleaned us all the equipment and reagents you have used during the course of the laboratory. Please note that marking schemes will reflect this. Please ensure that you work in a clean and safe manner at all times. Please note that practical schedules may include aspects of clean and safe working in the marking schemes. Laboratory books, such as Martindale, the Pharmaceutical Codex and British Pharmacopoeia, should not be used in the "working" area, i.e., at your bench. They should only be used away from areas where chemicals are being used. Please return all chemicals used in the laboratory to where you found them. If you persistently fail to adhere to this rule you will be excluded from the laboratory. Coats, bags and clothing may be stored in the area(s) provided and are not to be otherwise located in the laboratory. Students who put themselves or others at risk of injury by neglecting these rules will be immediately excluded from the laboratory and may face further disciplinary measures.

University of Hertfordshire School of Pharmacy Pharmaceutical Analysis, Production & Quality Control

LABORATORY RULES FOR THE SOLID DOSAGE FORM MANUFACTURING SUITE

Please note that these rules are in addition to, and not in place of, the general rules for laboratory safety, listed elsewhere in this document.

Due to the use of specialist pharmaceutical manufacturing equipment, you will not be able to enter the manufacturing suite once a practical has started. You will not be able to attend an alternative session (unless you have good reason for being late) and you may lose marks.
Please note that specific regulations will be used for each manufacturing session. You will be fully briefed of these at the start of the class, and the Health & Safety documents will be available to view during, and between, laboratory sessions. If you miss the start of a laboratory session without good reason you will not be omitted. Please note that, as you are involved in group work, such unprofessional behaviour may be potentially detrimental to your colleagues.

University of Hertfordshire School of Pharmacy Pharmaceutical Analysis, Production & Quality Control

Part One. Tablet Manufacture

Aims and objectives
The aims of these practical sessions are to illustrate the process involved in the production of conventional immediate release tablets formed by compression following a wet granulation process. It will also highlight your abilities to work in a group, and to fairly and maturely discuss working practices in this group, and to organise workloads fairly and equitably. At the end of this practical, you will be able to describe the formation of granules for tablet compression, describe the compression process of granules to form tablets, discuss the suitability of a pharmaceutical manufacturing facility, to calculate the amounts of drugs and excipients required for yours tablets, to discuss and contextualise the clinical relevance of the manufacture and evaluation processes, and to demonstrate effective and professional group-working.

Experimental Part One Tabletting Processing

The drug you will use is sodium saccharide. It is a white odourless powder that is soluble in 1.5 parts water, and has a pKa of 1.6. There are no known incompatibilities with this drug and any of the excipients. The aim of this practical is to produce a batch of tablets (weighing approximately 500 mg) each containing 33% w/w of the drug substance. The formula to be used is:

Drug Lactose Methycellulose (to be used as a 8% w/w solution) Magnesium stearate Disintegrant TOTAL

33% w/w q.s. 8% w/w 1% w/w ? % w/w to 500 mg

Notes: 1. You will need to choose the disintegrant for your formulation from either a conventional disintegrant, such as maize starch, or a superdisintegrant, examples are Ac-di-sol (Cross-linked sodium carboxymethylcellulose), EXPLOTAB (Sodium Starch Glycolate /cross-linked sodium carboxymethyl starch) and Kollidon CL (Crospovidone/Cross-linked polyvinyl pyrrolidone). We will discuss with you at the start of the practical and one disintegrant will be provided to each group. You will also need to decide the concentration of the disintegrant depending on the type you use, based on the knowledge from lectures and textbooks. 2. The disintegrant is often added in two stages. Half is added before granulation, and the remaining half is added after granulation and before compression; this is to ensure complete disintegration of both the tablet and the compressed granules contained therein. 3. The lubricant is added to the dry granules prior to compression and the weight of lubricant to be added in is based on the weight of the dry granules obtained after sieving. Each laboratory group will be given a different formulation, varying in the concentration and type of disintegrant used. This variation may have a significant, and specific, effect on the results of your evaluation tests. You will need to discuss this effect in your lab report.

University of Hertfordshire School of Pharmacy Pharmaceutical Analysis, Production & Quality Control

Summary of the manufacturing process

The process that you will carry out is a generalised wet granulation process, with the following steps: Check that the drying oven has been switched on and is at a suitable temperature. Please ask a member of technical staff if you have any issues. Weigh out the drug and excipients make sure you get the right amount of each formulation ingredient, and that you weigh out enough materials in total so that you can carry out all your evaluation tests next week. You should take into account that you may lose a significant amount of your formulation as you progress through this experiment (ideally aim for 700 - 800 tablets). Note: the binder methycellulose is to be used as an 8% w/w solution. The percentage of the binder in the formulation (6% w/w) is based on this solution. Mix this initial mixture in the v-shaped blender, add the binding solution, and mix for at least 5 10 minutes, checking after 5 minutes if possible. Transfer this mixture to the granulator make sure the mesh is fitted, and that you have something in which you can collect your granules. Dry your granules using the oven and the moisture balance Re-granulate, if required make sure the screen has been cleaned and is dry before being used again Sieve, using a suitable size of sieve Weigh out the remaining excipients (calculate the amount of lubricant to be used based on the dry granules obtained), add them to your granules, and mix in the cube mixer for five minutes. Make your tablets!

University of Hertfordshire School of Pharmacy Pharmaceutical Analysis, Production & Quality Control

Part Two. Tablet Evaluation

Please check StudyNet regularly to see which session you have been allocated.

Aims and objectives

The aim of this session is for your group to assess the quality of a batch of tablets (not necessarily the tablets that you made yourselves) by completing a series of BP tests.

The Tests
You are required to carry out six tests: Dissolution Uniformity of drug content Disintegration Friability Hardness Uniformity of tablet mass As part of your work, you should organise among yourselves how this work will be divided across your group. This will be discussed at the start of the laboratory class. Please be aware that you may be working with other groups of students, and that you may have to tailor your work plan accordingly. Please make full use of available resources, include any suitable Pharmacopoeia.

Experimental
Methods for disintegration, friability, hardness and uniformity of tablet mass are given in the lecture notes, to be found on the PAPQC StudyNet site. It is also advised that you check British Pharmacopeia for full details of the tests. Staff will assist you in the technical use of equipment in laboratories, but will not design or develop your protocols for you. Please refer to these notes before the practical, and bring them with you to the laboratory if you feel that you need them. Other methods are listed below.

Measurement of the uniformity of drug content.

This section outlines a method you can use in order to determine the uniformity of drug content in the tablets you are testing. You may still have to refer to the lecture notes to discuss the limits of the test, and whether or not the samples you are analysing pass or fail the test. The key steps you need to carry out are: Develop a method to extract the drug effectively from the tablets. Determine the concentration of the drug in the extraction solution.

Using a mortar and pestle, crush an appropriate number of tablets (one tablet in each mortar). Add approximately 5 mL per tablet of a 50:50 distilled water and methanol mixture to the crushed tablet and wash through a fan-folded filter paper into a 100 mL volumetric flask. Rinse the pestle and mortar several times with the 50:50 distilled water and methanol mixture and pass through the filter paper. Make the solution up to volume. (The crucial point is you dissolve the drug completely and transfer it into the flask completely) Examine this solution by UV spectroscopy. You may have to dilute your sample in order to fit in the concentration range of your calibration curve. If you have to dilute your sample please do so in a systematic manner, i.e., a 1-in-10 dilution, for example.

University of Hertfordshire School of Pharmacy Pharmaceutical Analysis, Production & Quality Control

Dissolution Testing
Use the dissolution apparatus as instructed by staff. Remember that you will have to analyse the contents of the dissolution sample at regular intervals by UV analysis, so please make sure that you, as a group, coordinate this experiment with the uniformity of drug content experiment, so that you can share the same analytical method. Take three tablets and place each of them into a metal dissolution baskets this will be demonstrated by a member of staff. Perform the BP Dissolution Test for 45 minutes see lecture notes for details. As part of this test please remember to, at the end of the experiment, inspect the contents of the metal basket and report your findings. Make sure you operate the experiment of the correct temperature and replace the sample you withdraw from the vessel with fresh medium. Determine the amount of drug in the sample using UV spectroscopy. Remember to filter your sample before you conduct the UV measurement. Development of the UV assay method You need to develop an UV assay method for both the uniformity of drug content and dissolution tests. Below are the key steps: 1). Determination of the drugs wavelength of maximum absorbance, max. Determine the max and record this value in your laboratory notebook. Use only this value for all subsequent UV analysis. 2). Production and validation of a calibration graph, or equivalent method, to allow a quantitative determination of drug concentration in your samples. The crucial part is to determine the concentration range of your calibration curve. Since this calibration curve will be used for both the uniformity of content and dissolution tests, the ideal is that this range will cover all the sample concentrations of both tests. If this cannot be achieved, you may need to choose the concentration range based on one test and dilute the samples of another test to fit into the range (choose wisely which test samples you want to dilute, so that you can minimize the number of dilutions you have to make). Now think about the sample concentrations of these two tests: Uniformity of content: based on the drug content in each tablet and the volume you dissolve them into, the theoretical concentration should be calculated. Dissolution test: you are taking samples regularly from the start to the complete dissolution, so your sample concentration range could be within 5% to 100% drug dissolved. Based on the drug content in each tablet and the volume of the dissolution medium, you should be able to calculate this range.

Once you decided the concentration range, you can make a stock solution and dilute it into the required concentrations within the range. Below are some guidelines: Stock solution: Dissolve 100 mg of the drug standard in a volume of 100 mL. Dilute this stock solution into the required concentrations within the concentration range you have chosen. Again, use a meaningful dilution technique in a systematic manner. Check what pipettes and volumetric flasks are available in the lab (if what you need is not available and they are reasonable, ask a member of technical staff for assistance).

This is an outline method only. Given your previous experience in the Analytical Science module, we have provided a brief outline method for you to consider. You are expected to research fully and justify your chosen method, and to have this ready for your Evaluation laboratory. You need to discuss your method with academic staff at the beginning of the lab before you start the experiments.