MDD Past Paper Qs Flashcards
Give a definition of thermogravimetric analysis (TGA) and describe its use in pre-formulation studies.
- Change in physical/chemical properties of materials is determined in a thermobalance as a function of a temperature or time
- E.g. Weight loss whilst melting
- Can provide information about absorption, desorption
- Used to determine selected characteristics that exhibit mass loss/gain (due to oxidation, loss of moisture)
- Can determine water content in materials
- Allows analysis of reactions with air, oxygen and other reactive gases
Max Williams, Chief Pharmacist at St Somewhere NHS Foundation Trust, is writing a job description for a new post, ‘Clinical Trials pharmacist’. Detail the 5 main areas of responsibility for a ‘Clinical Trials pharmacist’ which should be included in this job description, and include the list of activities associated with each responsibility.
- Oversees the staff involved in clinical trials ensuring they are appropriately trained
- Ensuring clinical trials is complying with current GMP guidelines (quality standards)
- Ensuring clinical trials are complying with current GCP guidelines (ethical and scientific quality requirements)
- Ensuring that IMPs are managed and dispensed to patients in accordance with the protocol
- Safeguarding patients and healthcare professionals by ensuring IMPs are appropriate for use and they are being handled and stored safely and correctly
- Review trial costs
In terms of ADME properties, what is the problem associated with propranolol and how do you overcome this?
- Propranolol has a high 1st pass rate resulting in low bioavailability due to the major metabolite, O-glucuronide
- Creation of a pro drug: Hemi-succinate ester is designed to block glucuronide formation
What is the rationale for a prodrug?
- Lack of site specificity
- Inadequate shelf life
- Inadequate dissolution rate
- High 1st pass metabolism
- Short duration of action
Briefly describe the aim(s) and methodology involved in Phase II clinical trials.
- 100-300 patients
- Aim is to find the efficacious dose
- Split into 2a (establishing efficacy) and 2b (establishing effective dose range)
- Initial assessment in patient population
- Randomised double blind clinical trial
- Placebo controlled
Give a brief outline of FIVE methods by which new drugs have been discovered in the past, or are discovered currently, providing examples of agents that have been discovered by these processes
- Serendipity: surprise discovery of drug:
- Penicillin
- Cisplatin- was discovered that running a current though a solution containing E.Coli with Pt electrodes resulting in cell arrest without killing the cell anticancer - Drug repositioning: Discovery of a side effect of one drug may be good for another indication. Viagra (sildenafil) was used as an anti-hypertensive but is now used for erectile dysfunction
- Metabolism studies: Diazepam Temazepam which showed a faster onset and shorter duration of action. It was discovered via HPLC
- Molecular Pruning: Taking a molecule that already exists and removing portions of it to determine what the pharmacophore is (however non-pharmacophore parts may be important for ADME). E.g. discovering methadone from heroin and then tramadol. Pharmacophores = tertiary nitrogen, aromatic ring, quaternary carbon
- Biochemical studies: Studying metabolic pathways, enzyme mechanisms, neurotransmitters etc. Examples:
- Antimetabolites: Methotrexate
- Antihistamines: Cetirizine
- Serotonin: SSRIs
- Noradrenaline: Salbutamol
Compare and contrast the evolutionary and search experimental design methods of optimising a tablet formulation. Use a specific example of each type of method design to construct you answer.
a) Evolutionary Optimisation
• Subdivided into simplex and newton
• Over times, things change gradually and the process is heavily repeated with small changes being introduced. This is continued until optimum is reached
• Defined set of rules
• Example Tablet making via a dial and each time you turn a notch it makes 10 tablets. You can change it bit by bit each time, such as an increase in compression so you are slowly making harder tablets.
• It does not need a model and involves trial and error
• Advantages quick to initiate, simple to perform, works immediately and requires little training
• Disadvantages Only changes one parameter, it is resource heavy, and has limited outputs. It will also only give you a specific answer and is not efficient with many variables involved
b) Search Optimisation
• Subtype: statistical experimental design
• You design a model and then you search within that model for an optimum
• Allows prediction from the model as you can extrapolate data
• Advantages multiple factor optimisation, complex outputs, and requires minimal requirements
• Disadvantages slow to initiate, complex to perform, a pilot and extensive training is required
• You evaluate the model and get a prediction from it
• Example for tablet optimisation
- Define the variables, such as constraint (compression force can be from 1-25)
- Want to optimise dissolution time
- What compression force is required to achieve the minimum dissolution time?
- Plot tablet compression force alongside dissolution time and use equation of the line to extrapolate data if necessary
• Important to know the reliability of your model – ONLY GOOD IF YOUR MODEL IS
• Can set goals you want to achieve for independent variables (parameters) and numerous goals can be combined
• Numerical output is designed, desirability is plotted and this then maximises output based on your criteria. Process is repeated to ensure global result
What is stastistical experimental design within search optimisation?
• Methods of designing experiments with multiple independent variables so that they can be analysed easily
• Error is assumed to be constant/predictable MAJOR disadvantage
• Example in tablet optimisation
- 3 independent variables (Mg St conc, Compression force, mixing time of excipients)
- Dependent variable = dissolution time
- Some experiments will be replicates of each other hence why there is actually a reduced number of experiments
• Can see interactions between variables (one affecting another) and can translate this into a mathematical equation that includes those two terms. For absolute independence, interaction =0
• Can be fully factorial design:
- e.g. 3 variables will have 23= 8 experiments, or 4 variables will have 24= 16 experiments
- Here, all main effects and interactions are separately estimated
- Some have lots of variables that will overlap and cause identical interactions which cannot be separated so they are termed as “Aliased” (if you structure all of the unimportant interactions to be aliased, then this can reduce the number of experiments)
• Can also get fractional factorial designs, such as half (dividing #experiments by 2) etc which can be used if you don’t want to take into account the interactions and can decrease the number of experiments
What is regression analysis?
- R2 value = multiple regression model
- r2 = non-multiple regression model
- Needs to be 4 dp
- Shows how close the model is to fitting the data points
- Power of the model
What is the resisual in terms of statistical analysis?
- Difference between the observed value of the dependent variable and the predicted value
- Each data point will have one residual
- Sum of residuals is used to calculate R2
- Should be minimised
What are partial derivatives used for?
• Are used to solve the equation for m and c to find the ideal model – can be performed using computer software (Excel)
How do we solve f(x) equation in non-linear functions?
- Must understand the function
- For a polynomial relationship, you use calculus
- Degree of polynomial function = highest value for n when n is not 0
- Use of the quadratic equation
Multivariant= use of several variables. Problems include:
- Complex multifactor problems
- Several local mima and maxima
- 1 global min/max
- 3 factor synthesis experiment
- In this case, it is better to solve problems through equations and not graphs. Computer is needed
What is Simplex method of evolutionary?
• No model required
• Factors = variables
• You have 2 factors and draw a triangle and optimise it
• If you had 3 factors, it would be (3+1) square etc. (but more than 2 factors, you will need to use software)
• Trying to find the optimum point on the axis via trial and error
1. Draw an axis with the two variables
2. Pick 3 random points and make a triangle
3. Perform experiment in 3 points and write down the output e.g. dissolution time
4. Then pick a new point to go away from the least wanted point (an equal amount so it is a reflection) and create a new triangle
5. If reflection results in a new minimum, plot further down the minimisation direction
- Must ALWAYS move away from undesirable points
- There is software that will colour code best and worst responses to create a contour plot
- Only searches for a pre-defined solution that you have set
Discuss the differences between herbal medicinal products and single chemical entity drugs, giving examples.
- Herbal medical products are a type of complementary and alternative medicines aimed to treat the patient holistically
- Less regulation and control such as less guarantee of skills, training, accountability
- Based on phytotherapy
- Examples of herbal medicinal products include homeopathy, and contain parts of plants or crude extracts
- Food supplements can be included as there is no distinction what it includes
- Available from practising herbalists, retail outlets, internet
- Less knowledge about these products and less evidence around them. They can be dangerous in terms of unknown drug reactions and the risk of intrinsic toxicity is high
- EU legislation has recognised “traditionally used” herbs as a new class of licensed medicines. It gives the guarantee of quality and safety NOT EFFICACY
- Has to have a license if it is making a medicinal claim
- Traditional Herbal Registration scheme is a product has been accepted a license
- Products can have a mixture of chemical substances (usually have several “actives”)
- Examples aloe vera, turmeric, valerian (for sleep)
- Easy to misidentify the plant and it may be infested with other organisms
- Single chemical entity drugs have an MHRA license and have had both in vitro and in vivo studies on them and have been accepted for a particular indication. Healthcare professionals are more confident in using them
