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Drug Development Process


PJ4012 – Drug Development

Developability of drugs This coursework is 1800±10%. Submission will be online on Turnitin folder on Blackboard. The date of submission will be on Sunday 6th December 11:59PM.

1. Introduction

Selective serotonin 2C (5-HT2C) antagonists, that enhance mesocortical dopamine signaling in the brain, are under development as fast-onset antidepressants. You are part of a drug development team that is working on a potential blockbuster drug for the treatment of depression. There are synthetic chemists, formulation scientists, pharmacologists, toxicologists, clinical scientists, regulatory affairs specialists, marketing and a principal scientist acting as the project manager who oversees the drug development process.


2. Objectives

• To develop skills to construct and provide a critical rationale for appropriate product design.

• To evaluate chemical data presented in the drug discovery process.

• To analyse physicochemical and pre-formulation data for the design of a suitable formulation.

• To be able to apply formulation science and principles to select appropriate excipients including solvents, suspending agents, viscosity emulsifiers, surface active agents, preservatives, colouring agents and sweeteners etc. to give desirable properties of a formulation of the given drug for the proposal of a “Dosage Form Nomination”.

• To devise an appropriate clinical trial strategy based on the given data.

3. To develop a working plan for the marketing authorisation application.Supporting data

Sections 3.1 to 3.4 provide information on the chemical studies (drug discovery), formulation development, in vitro and in vivo studies, and Marketing Authorisation Application of the investigational drug, OPTIMISIMX. [X refers to a to f, depending on your chosen candidate drug.]






3.1. Drug discovery

The chemists in your team have synthesised a series of compounds with potential antagonism to 5-HT2C receptor as an anti-depressant. The profiles of each of the possible candidate drugs (OPTIMISIMa, b, c, d, e and f) for development are shown in Table 1. One of these compounds needs to be selected to be progressed into Phase I clinical trials following suitable formulation testing.








Affinity towards h5-HT2C

high high high high high high

Selectivity vs h5- HT2B, h5-HT2A

>150 >80 >150 >100 >100 >100



Potent Inverse agonist/ant agonist


Potent antagonist


Potent antagonist


Potent antagonist


Potent antagonist


Potent antagonist

Oral activity 3

3 mg/kg 5.0 mg/kg 10 mg/kg 1mg/kg 2.0 mg/kg 15 mg/kg

MW (g/mol) 400.4 409.2 520.5 511.4 493.0 412.8

Half-life >3h ~4h >10h ~2h ~7h >10h

Salt form Di-HCl Mono-HCl Mono-HCl N/A Mono-HCl Mono-HCl

cLogP 4.2 4.8 2.3 6.1 3.5 -1.2

Metabolites 2 major 1 major 3 major 4 major 1 major N/A

Active metabolites none none 1 active 1 active none none

Cytochrome P450 Interaction

Inhibits 4

Inhibits 5

Weak inhibition


Weak inhibition


Induces 7


Tolerance None N/A Slight 8

None none none

Withdrawa l symptoms

None N/A N/A None slight none

Anxiogenicity None v. weak None weak none none





Teratogenicity 9

None None None Marginal 10

none none

Uticaria 9

Mild Mild None mild mild none

Relative Weight gain

None Not significant

Not significant

None none modest


Notes: 1. vs other h5-HT, dopamine and adrenergic receptors.


3. Rat model. 4. Partial of CYP2C9; 3A4, 3A5 and 3A7. 5. CYP2C9; 3A4, 3A5 and 3A7. 6. Weak at CYP2C9. 7. At high concentrations CYP2C9. 8. Develops after 12 days continuous dosing. 9. Rabbit model. 10. At highest dose of 30 mg/kg.


Based on the profiles presented, select ONE possible candidate compound to be taken to late-stage evaluation in the drug discovery process and justify your selection. Critically discuss the rationale and any adjustments that may need to be considered to take that compound forward for development if necessary. You should use references from journals / textbooks to help support your decision.


3.2. Formulation development

Following optimisation and further development of your chosen candidate drug, some further physical data and properties of the optimised candidate drug (a weak base) are shown in Table 2, and Figures 1, and 2. At this stage, the data provided in Table 2 and 3, Figures 1 and 2 are considered as the FINAL characteristics profiles.


Table 2: Characteristics of the chosen candidate drug.

pKa 8.1

Physical state at 25ºC Pink odourless, crystalline powder

Salt form Hydrochloride (non-hygroscopic)

Mesylate (hygroscopic)

Particle size 460 – 810 µm

Melting point 231ºC

UV absorbance (max) 520 nm

Chemical properties Stable between pH 3 – 8


Taste Strong bitter taste




















HCl salt

Mesylate salt







Figure 1. Solubility of hydrochloride and mesylate salts of the chosen candidate drug in purified water (pH 3) at different temperatures.



HCl sal t Mesylate sal t







Figure 2: Solubility of hydrochloride and mesylate salts of the chosen candidate drug in purified water (pH 8) at different temperatures.

Evaluate the physicochemical data provided for the optimised chosen candidate drug (OPTIMISIMX) and design a suitable formulation for this drug using ‘powder-in-a- bottle’ approach to be used for subsequent Phase I clinical trials. It is predicted that a daily dose of 30 mg may be suitable for clinical use. Based on the principles you have learnt so far about formulation science, you should first analyse the solubility and compatibility data. Then design a suitable formulation and explain the function of each excipient you have chosen. You must be able to justify your choice with supporting information. Finally you should consider the Dosage Form Nomination for subsequent development.

S o

lu b

il it

y (

m g

/m l)


o lu

b il

it y

( m

g /m





Avoid using excessive excipients unnecessarily. Only use essential excipients at suitable quantities and provide reasons for the quantities chosen.

Information about the necessary excipients and liquid dosage form design can be found in the following resources:

– Medicines Complete (online) – Handbook of Pharmaceutical Excipients (Raymond C Rowe) – The Science of Dosage Form Design (M. E. Aulton) – Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems

(Loyd V. Allen) – BP – – – – – (information on E numbers)


3.3. In vitro and in vivo studies

Both in vitro and in vivo animal studies on this leading compound showed promising 5-HT2C antagonism. Toxicological studies in rodents and dogs have been well tolerated with a predicted MTD of between 10-20 mg/kg. The candidate drug is 20% bound to plasma proteins. In vitro metabolism studies using human liver microsomes indicated that the candidate drug is a substrate of CYP 3A4. It is believed that the compound will be slowly metabolised and toxic metabolites are likely to be accumulated in patients with hepatic and renal impairment. A daily dose of 30 mg is the recommended clinical trial dose.

Devise an appropriate first-in-man study by describing the recruitment process (subject number, participant exclusion and inclusion criteria etc.), trial design (e.g. parallel or cross-over; randomization, blinding and masking), aims and objectives, and clinical outcomes / endpoints etc.


3.4. Marketing Authorisation Application

Data obtained from Phase I to III clinical trials supports the use of the drug for the treatment of depression.

Discuss the essential information that is required and relevant for this particular product for the submission of a Marketing Authorisation Application for a new active substance. E.g. if a drug name is required, then give it a drug name, rather than stating “a drug name is required”.




4. Support

You should use your lecture / workshop notes as well as the recommended textbooks and journal articles on drug discovery, pharmaceutical dosage form design, clinical trials, regulatory affairs and other relevant required texts to help you analyse the data. Please note that you may need to refer back to your learning in your MPharm Programme!

You may also find online searches such as Pubmed, ScienceDirect and Web of Knowledge useful for compiling references for writing this report. In particular, information from regulatory bodies such as the MHRA, FDA and the EMEA would also be useful to provide regulatory guidelines for the licensing and marketing of medicinal products. You are also strongly recommended to start doing the case study early before the deadline!


European Medicines Agency


US Food and Drug Administration


Association of the British Pharmaceutical Industry (ABPI)


International Conference on Harmonization (ICH) guidelines


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