2. Design in Pharmaceutical Product Development

1. 2. Design in Pharmaceutical Product Development

2. Design & Selection of Drug Substance

3. High Failure Rate • For every 10,000 NCE’s in Discovery • 10 enter pre-clinical development • 5 enter human trials • 1 is approved • Interestingly….. • Winning the lottery 1 in 5,200,000 • A Royal Flush in Poker 1 in 650,000 • Struck by lightning 1 in 600,000 • Appear on the Tonight Show 1 in 490,000 • Discovery to Market 1 in 10,000 • A son who will play pro football 1 in 8000 Make, screen & push more compounds into the pipeline!

4. Combinatorial Chemistry High Throughput Screening ‘HITS’ In Silico Screening Lead Compounds Developability Screens Optimisation DRUG PRODUCT

5. Combinatorial Chemistry & HTS: Poor Solubility Drug Discovery Before 1990 • lead compounds - drug like • potency improved by adding lipophilic moieties • low mol. weights circa.300 Drug Discovery After 1990 • advent of HTS • uses organic solvents to screen in vitro potency • lead optimisation occurs by • increasing mol. weight • lipophilicity BrickDust ! 40 % of compounds made each year are abandoned due to poor solubility-Giovani Sala, Elan Pharma

6. Preformulation and Developability Screening • Potency • Selectivity • Kinetics • Tissue penetration • Carcinogenicity • Physicochemical Properties Combinatorial Library Drug candidate Increase choice Improve selection hundreds of compounds evaluated in parallel using rapid, high throughput predictive assays

7. most least Solubility: Double Edged Sword • Relative difficulty in formulation design* • poor permeability • high first pass metabolism • poor chemical stability • low solubility • instability in GI fluids • high dosage • More flexibility in altering physical chemistry then physiology • absorption rate can vary from 0.001 - 0.05 min-1 i.e. x 50 • solubility can vary from 0.1 µg - 100 mg/ml i.e. x 1000,000 • target solubility is 1mg/ml (covers 1 mg to 500 mg oral dose) • Taken from a survey of formulation scientists • from 12 companies in Japan

8. GIT Physiology • Potential for chemical degradation under different pH’s • Changes in mucosal SA, presence of specific absorption windows • Influence of endogenous secretion along the GI-tract • Influence of gastric emptying, transit time and food dependency • Influence of hydration state and water availability along GI-tract • Pre-systemic availability – membrane/faecal binding & metabolism

9. Gastro Intestinal Tract conditions • Absorbing surface area of the colon (~0.3m2) very small c.f. rest of GIT (120-200m2) • High viscosity of lumen contents can compromise drug diffusion and therefore absorption • Long residence times (up to 16 hrs) • Densely populated with microbial flora

10. Predicting good oral absorption Volume (ml) required to dissolve the dose Dose/solubility ratio 250 500 1000 5000 10000 100000 Increasing permeability Jejunal solubility (e.g. FaSSIF ) Class I Class IIa Class IIb Good Difficult 10 (solubility limited) (dissolution rate limited) Good solubility and permeability Poor solubility, good permeability Particle size reduction or other bio-enhancement required Predicted Permeability in Humans (cm/sec x10-4) 1 Class IV Class III Poor solubility and permeability Good solubility, poor permeability Very poor Poor 0.1 Increasing solubility Increasing dose Butler&Dressman, JPharmSci. Vol 99, Issue 12, pp 4940–4954, Dec 2010

11. Physico-chemical methods for Boosting Oral Absorption* • Use a Form with higher solubility • more soluble polymorph • more soluble salt • amorphous c.f. crystalline form • Formulate so drug is in solution • Increase rate of dissolution • particle size *many principles applicable for parenteral delivery

12. Use a form with higher solubility

13. Crystal Form • Depending on crystallising conditions, actives may exhibit: • different habits • different polymorphs • solvates (solubility: organic > non solvate > aqueous solvate) • Polymorphs with lowest free energy (lowest solubility) tend to be more thermodynamically stable • metastable (more soluble) form less soluble form • smaller the difference in free energy the smaller the difference in solubility • could we use metastable form for safety assessment?

14. Serum Levels: Chloramphenicol Palmitate Effect of Polymorph Type

15. Crystal Form Bioavailability of tolbutamide polymorphs in dogs

16. Amorphous forms • Amorphous forms afford better solubility & faster dissolution rates c.f. crystalline forms • e.g. novobiocin, troglitazone • Amorphous forms can transform to a more stable, but less soluble crystalline state • tendency to transform is related to Tg & storage temp • Tg > 80oC for amorphous solids to remain stable at RT • for investigative studies low temperature storage to retain amorphous form is viable • can stabilise by formulating with excipients of higher Tg • PVP (Tg, 280oC) inhibits crystallisation of Indomethacin • melt-extrusion with PVP to form granules or tablets

17. Schematic view of Melt Extrusion Polymer Excipient Drug Shaping Device Tablets Granulation Granulator Pellets

19. pH adjustment & Salt Form • Any drug moiety with a pKa between 3-11 can potentially be solubilised by pH modification • Salt-Formation is an extension of pH adjustment. Most common forms are as follows: • acidic drugs: sodium>potassium>calcium • basic drugs: hydrochloride>sulphate>mesylate >chloride>maleate>tartrate>citrate • Salt-form requires agreement from all development parties • highly soluble form might be hygroscopic & unstable choose the best ‘all-rounder’

20. pH Solubility Profiles Weak Base Solubility=S0(1+10(pKa-pH) ) • Intrinsic solubility (S0) region – pH range in which compound is completely unionized and has the lowest solubility. • Ionized region – region around pKa of compound. At pKa are equal amounts of ionized and unionized forms of the compound in solution. For every pH unit change either side of the pKa gives a 10-fold change in amount of ionized drug in solution. Implications for lab measurements (pH control), & GI pH/ absorption. Compound precipitating in this region can be as free base or salt (depends upon the strength of solid-state interactions). • pHmax – the region where compound has maximum solubility (equilibrium solid state form will be a salt i.e. completely ionized drug associated with oppositely charged counter-ions). • Salt plateau – pH range in which the molecule is fully ionized and the salt solubility of the compound predominates. Solubility value is dependent upon strength of solid-state interactions with the counter-ion forming the salt. (Common ion effects & solvent can impact solubility.) SO= 0.528mg/ml pKa5.54 S0=intrinsic, solubility of free acid/base

21. Classical pH-Solubility profile S0=intrinsic, solubility of free acid/base

22. Salt Form Aqueous solubilities of RPR-127963 salts • Sulphate was progressed into development • Could use a more soluble form for investigative studies?

24. Formulate so drug is in solution

25. Solubilising Vehicles: organic solvents Organic solvents used in commercial parenteral formulations

26. Solubilising Vehicles Solvent/Cosolvent Issue Polyethylene glycol Laxative, LMW residues Propylene Glycol Dose limitation Ethanol Effect of chronic dosing Dimethyl Acetamide Irritation Oily Vehicles Solubilising limitations

27. Hydrophilic Exterior HO OH CH CH CH2OH Lipophilic Cavity • Complexation:Cyclodextrins • Enhance the Drug’s Water Solubility • Increase Drug’s Aqueous Solution Stability • Improve Solubility & Dissolution: Improve Oral Bioavailability • Effective Delivery Drug:CD Complex Lipophilic Drug 1:1 Complex

29. Complexation:Cyclodextrins Bioavailability of Sch-56952 (azole anti-fungal) in animals

30. Increase rate of dissolution

31. Solubility & Dissolution Rate Dissolution Rate D.Ae.Cs R Where D = Diffusion Coefficient Ae = Effective Surface Area Cs = Saturation Solubility R = Thickness of Diffusion Layer

32. Danazol Bioavailability (Dog)

33. The NanoCrystal™ Advantage • Rapamune (Wyeth) • Sirolimus • Immunosuppressant • was available as a sachet & reconstituted suspension • required storage in a fridge • Using Nanocrystals • possible to supply a solid oral tablet formulation • more stable • more convenient

34. Reference 14

35. Take Home Message Regardless of route a drug needs to dissolve first!

36. Formulating the drug substance into a Product

37. Requirements of a Dosage Form • Contains an Accurate Dose. • Makes drug available for absorption (oral dosage). • Is stable (retains quality). • Convenient to take or administer. • Is produced economically by an acceptable process.

38. “Know your Drug” Compensate for Deficiencies Addition of other materials Engineering Technologies Physical Modifications Optimise Levels of Excipients Effect on Drug “Know your Dosage Form” Formulation Development

39. Functions of Excipients • Compensate for deficiencies in the drug • Aid manufacture of the dosage form • Quality assurance and maintenance • Identity, patient acceptability • colour • taste • “Target” the drug to site of activity • absorption • site-specific delivery

40. Standards for Excipients • Must not interact (adversely) with the drug • Must not compromise safety or tolerance • Function in the manner intended

41. Factors affecting performance of oral dosage forms • particle size of active • granulation • granulating agents • mode of granulation • lubricant • type • degree of mixing • compression force • film coat All need to be evaluated: CMC section of regulatory submission

42. Phase I absorption, metabolism, tolerance (volunteers) Phase 2A “does the drug work” ? (efficacy) “ 2B dose/dose regimen Phase III “how good is it” Phase IV post-marketing studies Ideal that the same formulation is used at all stages Clinical Studies

43. Phase One Flexibility of Dose - powder in bottle - capsule - tablet Phase Two Range of Doses in “look-alike” units - tablet - capsule Phase Three Formulation for Marketing FDA will not consider tablets & capsules as bioequivalent! Tablets more popular than capsules (smaller & more stable) Dosage Forms for Clinical Programmes

44. What does a dose look like? Phase 2/3 Phase 4 stages Preclinical stage Phase 1 stage Phase 2 stage

45. Why do Formulations Change ? • Technical problems • Need to incorporate different doses • Nature of clinical programmes

46. Formulation and the Stock Market “To Merck’s dismay, Monsanto completed its clinical studies first. Among the reasons was a dosage glitch at Merck. The company found that, instead of 1000mg, the proper dose was 12.5-25mg. The pills that resulted were so tiny that Merck was afraid that Arthritis patients wouldn’t be able to pick them up. It enlarged them with edible filler but that caused another problem. The fiber turned out to slow the drug’s absorption. Three months were lost while researchers worked to fix this” Wall Street Journal January 10th 2001

47. Impact of changing dose! Very difficult to accommodate large changes in dose, as it will influence processing & manufacturing on scale-up