Preformulation Lecture - Solubility Analysis PDF

Solubility analysis  it is important for orally administered drugs or drugs needed to be converted into solutions.  It includes:  pKa determinations  pH solubility profile and common ion effects  Effect of temperature  Solubilization  Partition coefficient  Dissolution 1...

Solubility analysis  it is important for orally administered drugs or drugs needed to be converted into solutions.  It includes:  pKa determinations  pH solubility profile and common ion effects  Effect of temperature  Solubilization  Partition coefficient  Dissolution 1 23/4/2015  pKa determinations  It is important for drugs capable of ionization within a pH range (1-10), since solubility and then absorption can be changed by pH changes.  As example, for a weakly acidic drug with pka value greater than 3, the unionized form is present within the acidic contents of the stomach, but the drug is ionized predominantly in the neutral media of the intestine.  for basic drugs such as erythromycin, (pka ˜ 8-9), the ionized form is predominant in both the stomach and intestine. 2 23/4/2015  For w.a or w.b with pka 4.75 W.B. W.A. W.B. % of ionization 3 The equations?? H.W 23/4/2015  pka can be determined using potentiometric pH titration (the drug is dissolved in water forming either w.a or w.b. which titrated and pH recorded).  Conductivity, potentiometry and spectroscopy methods can be used. (all these at controlled conditions)??? 4 23/4/2015  pH solubility profile and Common ion effects  The solubility of an acidic or basic drug depends on the pka of the ionizing functional group and the intrinsic solubilities for both the ionized and un-ionized forms.  When the ionized or salt form of a drug is the solubility- limiting species in solution, the concentration of the paired counter ion (common ion) is usually the solubility determining factor. Ex. Salt of basic amine BH+ Cl- + - + - + - [BH Cl ]solid [BH ] + [Cl ] , Ksp=[BH ][Cl ] - [Cl ] increase total solubility decrease  Then, the solubility affected by pH, counter ion conc., drug conc., ionic strength, temp., and aqueous media composition. 5 23/4/2015  For drug (Doxycycline, pka 3.4), there is common ion effect for an amine hydrochloride salt on solubility.  The solubility in aqueous medium (pH 2 or less) logarithmically decreased as a function of pH (which was adjusted with hydrochloric acid) because of corresponding increases in the chloride ion concentration.  In gastric juice (pH, 1-2 and [Cl-]= 0.1-0.15M), doxycycline hydrochloride dihydrate has a solubility of about 4mg/ml, which is a factor of 7 less than its solubility in D.w.  In addition to that, protonated form (of solubility product) of doxycycline can form dimeric species (due to self association) at certain pH. 6 23/4/2015  Effect of temperature 7 23/4/2015 The heat of solutions are varied with variation of drug chemical form (salt or free form).(T or F)? 8 23/4/2015  Solubilization How we can increase the solubility extent in water? Addition of co-solvent (depending on chemical structure of drug?). Addition of surfactant Complexation 9 23/4/2015  Partition coefficient 10 23/4/2015  Dissolution 11 23/4/2015  Experimentally, a constant S.A. is obtained by compressing powder into a disc of known area with a die and punch apparatus. 12 23/4/2015  Stability analysis  Is usually the first quantitative assessment of chemical stability of a new drug.  It includes both solution and solid state experiments under conditions typical for the handling, formulation, storage and administration of a drug candidate.  Generally, it includes: 1.Stability in toxicology formulations 2.Solution stability 3.Solid state stability 13 23/4/2015  Stability in toxicology formulations  A drug is administered to the animal in their feed, or by oral gavage of a solution or suspension of the drug in an aqueous vehicle.  Water, vitamins, minerals (metal ions), enzymes and a multitude of functional groups are present in feed, which can severely reduce the shelf- life of a drug.  Solution and suspension formulations are checked for ease of manufacture and then stored in flame- sealed ampoules at various temperatures. 14 23/4/2015  Solution stability  It is important for identification of conditions necessary to form a stable solution including the effects of (pH, ionic strength, co-solvent, light, temperature and oxygen).  pH for maximum stability is determined using different types of buffers at constant conditions(?). Acid-base catalysis Rate (K) (pH rate profile) 15 23/4/2015  Ionic strength depends on the molar concentrations of ion (with valency), it must be constant specially for injectable solutions (about 0.15).  Co-solvent can affect solubility and stability (hydrolysis prevention), solvents effects originated from dielectric constants values?, toxicity and compatibility. So the selected cosolvent must be selected at controlled conditions like (temperature not causes evaporation, sealing/packaging).  The studies include photodegradation and oxidation depending on the drug, so if found (must be prevented ? how). 16 23/4/2015 Then, Arrhenius equation ? is used for studying the effect of temperature on solution at controlled conditions. The fractions of remaining drugs are assayed using UV, HPLC (the best?). After determination of the rate constant at 25°C, the shelf life can be calculated using the equation: t10% = 0.105/K25  Depending on the results, we can decide if, the drug can prepared in soluble, stable and effective form or not. 17 23/4/2015 18 23/4/2015  Solid state stability  Includes identification of the suitable conditions for storage of solid drugs and drug-excipients compatibility.  Solid state changes may include changes in the bulk properties.(so must be assayed as before)  The reaction rates are much slower and more difficult to interpret.(why?)  Generally, it involve placing of a new drug (certain weight) in open screw cap vials and then exposed directly to a variety of temperatures, humidities, and light intensities for long period of time. 19 23/4/2015 20 23/4/2015 21 23/4/2015  Effect of oxygen and light can be studied for effected drugs and then protected within study at various (T and RH).  RH has its reaction rate constant (KH), so as increased by increasing of water in atmosphere as the degradation increased.  Solid drug-excipient compatibilities (physical or chemical ) must be evaluated using different assay methods for pure drug alone, physical mixtures (at certain ratio) and formulas. The end 22 23/4/2015