Solubility Enhancement Strategies (I, II, III) PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Solubility Enhancement Strategies (I, II, III) Course: Masters in Pharmacy (MPharm), BSc Advanced Therapeutic Technologies Module: Medicines 1 Lecturer: Dr Sam Maher LEARNING OUTCOMES 1. Highlight the pharma...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Solubility Enhancement Strategies (I, II, III) Course: Masters in Pharmacy (MPharm), BSc Advanced Therapeutic Technologies Module: Medicines 1 Lecturer: Dr Sam Maher LEARNING OUTCOMES 1. Highlight the pharmaceutical problem posed by poor solubility 2. Describe the strategies used to improve drug solubility 3. 4. 5. WHAT IS LOW DRUG SOLUBILITY? Many receptor mediated interactions are (in part) by hydrophobic interactions (drug:receptor) High lipophilicity is a common problem in pharmaceutical drug development 40% of marketed drugs have low aqueous solubility Up to 75% of compounds in currently under development Risk: low and variable absorption SOLUBILITY OF THE TOP 200 MARKETED ORAL DRUG PRODUCTS EXAMPLES OF DOSE, SOLUBILITY AND VOLUME REQUIRED FOR A RANGE OF POORLY WATER SOLUBLE DRUGS Drug Dose Solubility Volume Absorption required for complete solubilisation Piroxicam 20mg 7 mcg/mL 2857 Low variable Digoxin 0.5mg 24 mcg/mL 21 Good Griseofulvin 500mg 15 mcg/mL 33,333 Low, variable Chlorthiazide 500mg 780mcg/mL 636 Intermediate  BRICK DUST AND GREASE BALLS BRICK DUST Hydrophobic and exhibit strong intermolecular forces in the solid state Poorly soluble in aqueous and non- aqueous solvents GREASE BALLS Hydrophobic solutes where solubility is not limited by solid state properties Soluble in non-aqueous solvents Hydrophobic and lipophilic STRATEGIES TO ENHANCE SOLUBILITY 1. MANIPULATION OF pH 2. SALT FORMATION 3. CRYSTAL ENGINEERING 4. PARTICLE ENGINEERING 5. CO-SOLVENCY 6. SOLID DISPERSIONS 7. SURFACTANT SOLUBILISATION 8. PRODRUG 9. DRUG DERIVATION 10.LIPID BASED FORMULATIONS 11.MANIPULATION OF pH 12.LIPID-BASED DRUG DELIVERY SYSTEMS 13.INCLUSION COMPLEXES 14.EMERGING STRATEGIES  MANIPULATION OF pH Adjusting solution pH provides an effective means of increasing the proportion of a weakly acidic and weakly basic drug that is present in the more polar ionised form Effectiveness of pH manipulation is a function of pKa and Log D Useful when preparing solution dosage forms (e.g. for parenteral delivery) 75% of drugs are weak bases 20% of drugs are weakly acidic 5% non-ionic and amphoteric  PHARMACEUTICAL SALTS In many ways salts of weak acids and bases are the solid state equivalent of pH adjustment. Salts are formed by an ionic interaction between weakly acidic or basic drugs and an oppositely charged basic or acidic counterion. When placed in water the salt form dissociates and the oppositely charged counterion which they where derived from shift the pH of the solution to provide an analogous endpoint to that obtained by pH adjustment. The salt form also alters the crystal lattice A drug may exist in several salt forms which have different physicochemical properties Regulatory agencies do not consider different salt forms as equivalent SALT FORMATION WEAK ACIDS SALT FORMATION WEAK BASES COMMON COUNTER IONS IN ORAL DELIVERY BASIC COUNTERIONS ORAL % ACIDIC COUNTERIONS ORAL % Sodium 65 Chloride 57 Potassium 13 Sulphate 8 Calcium 12 Maleate 7 Magnesium 3 Mesylate 4 Tromethamine 3 Bromide 4 Tartrate 3 Phosphate 3 Succinate 2 Tartrate 3  SALT FORMATION AND SOLUBILITY K Penicillin Penicillin Potassium Mw: 334 Da Mw: 372 Da Water solubility: 210mg/1000mL Water solubility >100mg/1mL Acids donate protons to hold a formal anionic charge (conjugate base form) making them soluble in the salt form (e.g. Na salt)  SALT FORMATION AND SOLUBILITY Propranolol Propranolol HCl Mw: 259.34 Da Mw: 295.8 Da Water solubility: 1g/956mL Water solubility 1g/20mL Bases accept protons to hold a formal cationic charge (conjugate acid form) that makes them soluble in the salt form (e.g. hydrochloride salt)  SALT FORMATION AND SOLUBILITY Morphine base Morphine sulphate Mw: 285.34 Da Mw: 668.83 Da Water solubility: 149mg/L Water solubility 10g/L  SALT FORMATION CAN INCREASE OR DECREASE SOLUBILITY TO TAILOR RELEASE Drug Solubility (mg/mL) Tetracycline 1.7 Tetracycline HCl 10.9 Tetracycline phosphate 15.9 Erythromycin 2.1 Erythromycin Estolate 0.16 Erythromycin stearate 0.33 Erythromycin lactobionate 20  THE LIMITATIONS OF SALT FORMS CASE: A sodium salt of an acidic drug (pKa 5.5) dissolves in a dissolution bath at the pH of the stomach (~pH 2) and subsequently forms a fine precipitates (comes out of solution as solid particles). Comment on this phenomena……  COMMON ION EFFECT Hydrochloride salts and sodium salts of weak acids and weak bases are common drug salts because they are physiologically abundant (safe) These ions are abundant in blood and the GI tract and these ions (Cl, Na) can suppress the solubility of the drug that they are intended to enhance through the common ion effect The common ion effect is the Equilibrium will shift so that common ion in displacement of an ionic solution is reduced, leading to precipitation equilibrium by addition of more than one of the ions involved  CASE DRUG AND SALT FORMS The two most common oxidation states of iron are the ferrous [Fe(II)] and ferric [Fe(III)] forms Fe2+ Fe3+ FABS: 10-15% FABS: 2.5-5% Relatively good solubility Relatively poor solubility Solid form Solid form Ferrous sulphate (Ferrograd® Tablets) Fe(III) Polymaltose Complex (Ferrum®) Ferrous fumarate (Galfer® Capsules) Ferrous Gluconate (Floradix® Liquid) Side effects Constipation Side effects Heart burn Constipation Abdominal pain Heart burn Nausea Abdominal pain Nausea Prevalence of side effects Ferric iron: 7% Prevalence of side effects Ferrous sulphate: 31.6% Ferrous fumarate: 44.8% ADDITIONAL FUNCTIONS OF SALT FORMATION Sustained release (depot injection, procaine penicillin) Taste masking (e.g. Erythromycin ethyl succinate) Improved chemical stability (Erythromycin propionate) Process optimisation (flowability, compaction) PHYSICAL PROPERTIES OF PHARMACEUTICAL SALTS Salt properties vary depending on the drug, salt properties and solvent used to isolate the salt Salts exist in many chemical forms – Crystalline form – Crystalline solvates/hydrates – Liquid crystals – Irregular amorphous states Crystals typically have greater physical stability compared with drug base Hygroscopicity can be an issue for salt forms Drug bases with low melting point are often soft and plastic which creates problems in formulation (disintegration, friability, uniformity) and process (flowability, compressibility, dissolution) development  SALT FORMATION CAN INCREASE OR DECREASE SOLUBILITY TO TAILOR RELEASE ADVANTAGES DISADVANTAGES Altered solubility and dissolution Only ionisable drugs Controlled release Decreased % active Improved thermal, hydrolytic & photostability Increased potential for formation of solvates and polymorphs Improved processability Salt corrosion Improved permeability Additional processing step in production Improved organoleptic properties Possible for release of hydrohalide gas resulting in reaction with excipients or processing chemicals Reduced pain on injection  CRYSTAL ENGINEERING Crystal engineering: Deliberate design and control of molecular packing within a crystal structure with the intention of generating solid that shows a particular and desirable characteristic Any manipulation that results in altered crystal packing – Traditional approaches: salt, solvate, polymorph screening – Recent approaches: cocrystals – Particle engineering – HELPS TO OVERCOME SOLUBILITY LIMITATIONS RESULTING FROM STRENGTH OF THE CRYSTAL LATTICE BONDING IN A CRYSTAL VAN DER WAALS FORCES (0.5-2 kJ/mol) π- πSTACKING (0.5-2 kJ/mol) ELECTROSTATIC INTERACTION (0.5-2 kJ/mol) HYDROGEN BONDING (5-30 kJ/mol) IONIC INTERACTIONS (150 kJ/mol) Higher the lattice energy the greater the stability (and lower solubility) PREPARATION OF A HIGH ENERGY POLYMORPH CRYSTAL OFTEN HAS MODEST IMPROVEMENT OF SOLUBILITY (DUE TO RECRYSTALISATION) BUT GREATLY IMPROVED ABSORPTION, BUT CAN SUFFER FROM INSTABILITY INFLEUNCE OF POLYMORPH SELECTION ON DISSOLUTION, SOLUBILITY AND ABSORPTION OF RIFAXIMIN  COCRYSTALS COCRYSTALS: Mixed crystals consisting of two or more molecular species (that alone are solid at ambient conditions) held together by non-covalent and non-ionic forces Constitute a complex between drug and cocrystal former. Similar to salt formation, only proton exchange does not occur. Stabilisation of high energy crystal form that prevents unstable polymorphs from reverting to their stable form, while retaining improved solubility/absorption Dramatic increase in dissolution over simple crystals Some coformers can purposefully lower solubility EXAMPLE COCRYSTAL COFORMERS DRUG COFORMER INDOMETHACIN SACCHARIN EXEMESTANE MALEIC ACID COSOLVENTS COSOLVENTS: water miscible organic solvents that are widely used to increase solubility of poorly water soluble substances. Suited to drugs that lack ionisable functional groups Typical log P between 1-3 Blending alters the dielectric constant such that the solvent polarity matches the drug polarity (like dissolves like), and reduces interfacial tension Safety and pharmacological action can be a concern (e.g. haemolysis) Occasionally a non-aqueous co-solvent blends are used Solubility in mixed solvents is difficult to predict A drug will often have higher solubility in a solvent mixture than neither neat solvent  COMMON COSOLVENTS IN PARENTERAL DELIVERY COSOLVENT DRUG FORMULATION ROUTE PROPYLENE GLYCOL (40%) DIAZEPAM VALIUM IV bolus (1mL/min) ETHANOL (10%) ETHANOL (49%) PACLITAXEL TAXOL IV infusion (dilute to