Importance of partition coefficient in formulation development

Importance of partition coefficient in formulation development : 

Importance of partition coefficient in formulation development 9/25/2011 Mr. sagar Vekariya M.Pharm (Pharmaceutics) Babaria Institute of Pharmacy

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The partition coefficient The lipophilicity of an organic compound is usually described in terms of a partition coefficient, log p, which can be defined as the ratio of the concentration of the unionized compound, at equilibrium, between organic and aqueous phases: Log P values have been studied in approximately 100 organic liquid–water systems. Since it is virtually impossible to determine log P in a realistic biological medium, the octanol:water system has been widely adopted as a model of the lipid phase (Leo et al. 1971). It has been shown that many biological phenomena can be correlated with this parameter, such that “quantitative structure activity relationships” (QSARs) may be deduced. These include solubility, absorption potential, membrane permeability, plasma protein binding, volume of distribution and renal and hepatic clearance. 9/25/2011

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Generally, compounds with log P values between 3 and 6 show good absorption, whereas those with log P greater than 6 or less than 3 often have poor transport characteristics. Highly non-polar molecules have a preference to reside in the lipophilic regions of membranes, and very polar compounds show poor bioavailability because of their inability to penetrate membrane barriers. Thus, there is a parabolic relationship between log P and transport. 9/25/2011

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Method to determine log P The most common method for determining partition and distribution coefficients is the shake flask method . In this technique, the candidate drug is shaken between octanol and water layers, from which an aliquot is taken and analyzed. The value of the partition coefficient is affected by factors such as temperature, insufficient mutual phase saturation, pH and buffer ions and their concentration, as well as the nature of the solvents used and solute examined (Dearden and Bresnen 1988). Other methods: HPLC method Membrane partition method Computer method Atom based method 9/25/2011

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The measurement of partition coefficient has no of application: 1) Solubility: aqueous and in mixture of solvents 2) Drug absorption in vivo: used in a homologous drug series for structure activity relationship (SAR) 3) Extraction: Particularly from biological fluid samples. 4) Partition chromatography (reverse phase): Choice of column (HPLC) or plate (TLC) and mobile phase (eluant) 5) Emulsions: to establish effective levels in the aqueous phase. This particularly applies to preservatives. 6) Release from semisolids: dissolution from topical dosage forms and suppository fatty bases. 7) Solubilization: an increase in solubility by entrapment in micelles still requires effective levels in the external aqueous phase. 8) Complexation: certain complexes partition difficulty to the substrate and complexing agent. This change in lipophilicity will affect the activity of the drug and can also be used to measure the extent of complexation. 9/25/2011

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Effect of drug lipophilicity (log P) on drug solubility in aqueous cosolvents 9/25/2011

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Discriminating power of partitioning solvent as a function of their water capacity (mg%) 9/25/2011

Needs of Drug Solubilization: 

Active Ingredients in development are poorly soluble Poor solubility has become a major challenge in drug delivery as 90% of the active ingredients are proved to be having low aqueous solubility issues and this proportion is still growing Time and cost involved with screening for salts Hydrophobic nature of the New Chemical Entity (NCE) prompts for screening of its various salts with similar safety and efficacy and a better solubility/bioavailability Salt selection is a time consuming process and delays the drug development , thereby adding to the development cost of a drug Failure of drugs to move from preclinical to phase I Nearly 75% of preclinical stage drugs do NOT move to phase I Around 39% of these failures are attributed to poor drug-like properties of the drugs (implying low solubility) Increase in number of poorly soluble drugs in the market About 40% of drugs currently on the market exhibit poor solubility leading to poor dissolution kinetics and suboptimal bioavailability, in other words low product efficacy Needs of Drug Solubilization Issue Effect on R&D Effect on Pipeline Impact on Market Size 9/25/2011

drugs in preclinical stage: 

Poor Drug like Properties 39% N = 3,900 Molecules promoted from preclinical to phase I 25% Molecules failed in preclinical 75% High Toxicity 11% Adverse Effects 10% Low Efficacy 30% Others 10% drugs in preclinical stage WHY DO THEY FAIL? 9/25/2011

Facts & Findings: 

Facts & Findings > 40% of marketed drugs are poorly water-soluble [Lipinski CA, 2001; Giliyar C, 2006] Among the US pharmacopeia, the share of poorly water-soluble drugs is > 30%. [ Giliyar C, 2006]. 60% of drugs coming directly from synthesis have a solubility below 0.1 mg/ml. [ Merisko .E, 2002]. Poorly soluble drugs are a general problem in pharmaceutical drug formulation. [R.H. Muller, 1998] 9/25/2011

Approaches on basis of bcs classification classification: 

Approaches on basis of bcs classification classification SOLUBILITY High Low High Low 9/25/2011

Approaches for Delivery of Poorly Soluble Drugs : 

Approaches for Delivery of Poorly Soluble Drugs A) Size Reduction Jet-milling High energy ball milling Spray drying Super critical fluid extraction Nanosuspension by Homogenization Technology B) Inclusion Complex 9/25/2011

Approaches for Delivery of Poorly Soluble Drugs : 

C) Lipid Based Delivery Systems Microemulsion Lipid Emulsion Technology Self Dispersing Lipid Formulations Oily solution or Lipid based excipients D) Micellar Technologies Mixed micelles Polymeric Micelles E) Solid Dispersion Technology F) Osmotic Drug Delivery Approaches for Delivery of Poorly Soluble Drugs 9/25/2011

Decision tree for selection of formulation approach : 

Decision tree for selection of formulation approach 9/25/2011

Jet Milling : 

Jet Milling Relies on particle-particle interaction Narrow size distribution Minimal heating Mean size 1-10 microns 9/25/2011

MEDIA MILLING (NANOCRYSTAL TECHNOLOGY): 

MEDIA MILLING (NANOCRYSTAL TECHNOLOGY) The high energy and shear forces generated by impaction of the milling media break the microparticulate drug into nano -sized particles. composed of glass, zirconium oxide or highly cross-linked polystyrene resin. Formerly, the technology was owned by the company NanoSystems but later it has been acquired by Elan Drug Delivery. Rapamune by Wyeth and Emed By merck are Elan’s Naosystem based product in market. 9/25/2011

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Spray drying: 

Spray drying Spray drying is a commonly used method of drying a liquid feed through a hot gas. Typically, this hot gas is air but sensitive materials and solvents like ethanol require oxygen-free drying and nitrogen gas is used instead. 9/25/2011

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Super critical fluid TECHNOLOGY : 

Super critical fluid TECHNOLOGY The most widely employed methods of SCF processing for micronized particles are rapid expansion of supercritical solutions (RESS) and gas antisolvents recrystallisation (GAS). Supercritical fluid is any substance at a temperature and pressure above its thermodynamic critical point. It has the unique ability to diffuse through solids like a gas, and dissolve materials like a liquid. Carbon dioxide (CO 2 ) is commonly used SCF due to its favourable processing characteristics like its low critical temperature ( Tc = 31.1-C) and pressure (Pc = 73.8 bar) 9/25/2011

Schematic diagram of Supercritical fluid particle former : 

Schematic diagram of Supercritical fluid particle former 2 1 3 4 5 6 7 8 9 10 11 An apparatus for making liposomes is schematically described here, which comprised of the following elements: CO2 storage take 1, Heat exchanger 2, CO2 flow pump 3, Heat exchanger 4, a high pressure vessel or chamber 5, Co-solvent container 6, Co solvent pump 7, a second vessel 8, Automated Back pressure regulator 9, solvent collection valve 10 and Co-solvent spraying nozzle 11. Principle 9/25/2011

Homogenization Technology: 

Homogenization Technology The suspension is forced under pressure through a valve that has nano aperture which causes bubbles of water to form which collapses as they come out of valves. This mechanism cracks the particles. Useful for formation of very dilute as well as highly concentrate nanosuspension Aseptic production possible. Disso-cubes and Nanoedge Technology 9/25/2011

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Micro Nano 9/25/2011

Complexation: 

Complexation Complexation is the association between two or more molecules to form a nonbonded entity with a well defined stichiometry . Complexation relies on relatively weak forces such as London forces, hydrogen bonding and hydrophobic interactions. CAPSITOL® CyDex and CAVAMAX® by Wacker-Chemie GmbH. Types Examples Inorganic I B - Coordination Hexamine cobalt(III) chloride Chelates EDTA, EGTA Metal-Olefin Ferrocene Inclusion Cyclodextrins, Choleic acid Molecular Complexes Polymers 9/25/2011

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Cyclic oligosaccharides Forms water-soluble inclusion complexes >30 products containing cyclodextri –drug complexes on the market [ Loftsson T. et al 2005] 9/25/2011

marketed products arising from the cyclodextrin inclusion technique: 

marketed products arising from the cyclodextrin inclusion technique Drug/cyclodextrin Market name Company Piroxicam / β- cyclodextrin Cycladol ® Brexin ® Brexidol ® Masterpharm Robapharm Launder Itraconazole / HP- β- cyclodextrin Sporanox ™ Janssen Benexate / β- cyclodextrin Ulgut ® Lonmiel ® Teikoku Shionogi PGE/ β- cyclodextrin Prostandin ® Prostavasin ® Ono Schwarz Pharma Dexamethasone glyteer / β- cyclodextrin Glymesason ® Fujinaga Iodine/ β- cyclodextrin Mena-Gargle® Kyushin Nitroglycerin / β- cyclodextrin Nitropen ® Nippon Kayaku 9/25/2011

Microemulsion : 

Microemulsion Microemulsions can be defined in general as thermodynamically stable, isotropically clear dispersions of two immiscible liquids stabilized by interfacial films of surface-active molecules The microemulsions are formed by simple agitation of oil, water, surfactant and co-surfactant. The formation of microemulsion is spontaneous and does not involve the input of external energy. Reverse (w/o) Direct (o/w) 9/25/2011

Self Dispersing Lipid Formulations: 

Self Dispersing Lipid Formulations Contain oil and a surfactant mixture into which the drug is incorporated. They emulsify when mixed with aqueous environment .The self-emulsification process is specific to the particular pair of oil and surfactant, surfactant concentration, oil/surfactant ratio, and the temperature at which self-emulsification occurs. PORT (Programmable Oral Release Technology) Systems formulate poorly soluble drugs as proconcentrates (concentrates) that will form microemulsion in vivo leading to enhanced bioavailability of such drugs. IDD-SE® technology constitutes a SEDDS where surface stabilized sub micron sized particles or droplets are self generated when the dosage form is exposed to the aqueous environment of the GIT. 9/25/2011

Oily Solution or Lipid-based excipients: 

Oily Solution or Lipid-based excipients Oily solutions contain poorly water soluble drugs just dissolved in oil. Usually encapsulated in hard or soft gelatin capsules. After oral administration, when the oily solution reaches the duodenum, the oil is emulsified by the bile salt/lecithin micelles in the intestinal fluid. Calcitrol in fractionated coconut oil triglyceride ( Rocaltrol ®, Roche), antiemetic dronabinol in sesame oil ( Marinol ®, Solvay Pharmaceuticals) which are contains in soft gelatine capsules. 9/25/2011

Micellear Technology : 

Micellear Technology Micelles are aggregates of surfactant(s) which self assemble above a specific concentration in water. The surfactant(s) molecules have both lipophilic and hydrophilic properties which arrange into very small colloidal particles in water. Soak up greasy and lipophilic material by solubilization within the lipophilic region of the structures. Docetaxel Injection Concentrate ( Taxotere ®, Aventis) and amprenavir oral solution and capsules ( Agenerase ®, GSK) are micelle formulations used to solubilize the poorly soluble compounds . 9/25/2011

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A- Micelle (non-polymeric) composed of amphiphilic surfactants, B- Polymeric micelle composed of amphiphilic block copolymers Mixed Micelle Formation Process A B 9/25/2011

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Solid Dispersion Technology: 

Solid Dispersion Technology Consist of a hydrophilic carrier incorporating very small particles of the lipophilic drug, preferably in the amorphous state. Eg . Inulin glasses/Sugar glasses Inulin is a naturally occurring fructose polymer Mixing an inulin solution with a drug solution followed by freeze-drying under appropriate conditions, results in the formation of a sugar glass. Protect the compound against physical and chemical degradation. 9/25/2011

Osmotic Drug Delivery : 

Osmotic Drug Delivery Using osmotic pressure as the energy source, the semipermeable membrane controls water inflow, generating hydrodynamic pressure inside the device and, thereby controlling drug delivery. All these technologies have in common the ‘semi permeable’ membrane controlling the drug delivery rate Osmotic pumps offer a highly effective method of delivery and are capable of linear release for even nearly insoluble drugs. Complex manufactureing process Eg Procardia XL® Glucotrol XL® 9/25/2011

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Elementary Osmotic Pump Semipermeable membrane with single orifice core containing API and Osmogen . The water penetrates inside the dosage form. This results in formation of saturated solution of drug within the core, which is dispensed at a controlled rate from the delivery orifice present in the membrane. EnSoTrol ® 9/25/2011

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L-OROS TM Oros ® Push- Pull TM Double layer Tab ctg. API ± osmogens and Polymeric osmotic layer coated with semi-permeable membrane. The drug can be delivered via suspension, it can deliver drugs with solubility extremes, and water-insoluble drugs up to a maximum of 200 mg poorly soluble drug 9/25/2011

Nanotechnology approaches to improve the solubility of hydrophobic drugs: 

Nanotechnology approaches to improve the solubility of hydrophobic drugs Company Technologies Description Elan NanoCrystal NanoCrystal drug particles (<1,000 nm) produced by wet-milling and stabilised against agglomeration through surface adsorption of stabilisers. Baxter Nanoedge Nanoedge technology: drug particle size reduction to nanorange by platforms including direct homogenisation, microprecipitation , lipid emulsions and other dispersed-phase technology Eurand Biorise Nanocrystals /amorphous drug produced by physical breakdown of the crystal lattice and stabilised with biocompatible carriers ( swellable microparticles or cyclodextrins) BioSante CAP Calcium Phosphate-based nanoparticles: for improved oral bioavailability of hormones/ proteins such as insulin; also as vaccine adjuvant . 9/25/2011

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Company Technologies Description American Bioscience NAB Nanoparticle Albumin-Bound technology: injectable suspension of biocompatible protein with drug improves solubility/removes need for toxic solvents; eg paclitaxel -albumin nanoparticles Skye Pharma IDD Insoluble Drug Delivery: micro-nm particulate/droplet water-insoluble drug core stabilised by phospholipids; formulations are produced by high shear, cavitation or impaction pSivida BioSilicon Drug particles are structured within the nano -width pores of biocompatible BioSilicon microparticles , membranes or fibres; gives controlled release/improves solubility of hydrophobic drugs iMEDD NanoGate Silicon membrane with nano -width pores (10-100 nm) used as part of an implantable system for drug delivery and biofiltration PharmaSol NLC8 Nanostructured Lipid Carriers: nanostructured lipid particle dispersions with solid contents produced by high-pressure homogenisation; lipid-drug conjugate nanoparticles 9/25/2011

References: 

References Lipinski CA, Lombardo F, Dominy BW, Feeney PJ: Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv . Rev. ( 2001 ) 46 : 3 -26 Giliyar C, Fikstad DT, Tyavanagimatt S: Challenges and opportunities in oral delivery of poorly water-soluble drugs. Drug Deliv. Technol. ( 2006 ) 6 : 57 -63. Merisko E & Liversidge Nanocrystal : Resolving pharmaceutical formulation issues with poorly water soluble compounds. In J. J. Marty (Eds.). (2002), Particles ( pp.49 ) . Marcel Dekker, Orlando. R.H. Muller, S. Benita, B. Bo¨hm (Eds.), Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs, Medpharm Scientific, Stuttgart, (1998). Loftsson T, Jarho P, Másson M, Järvinen T: Cyclodextrins in drug delivery. Expert Opin . Drug Deliv . ( 2005 ) 2 : 335 -351 . http://www.fda.gov/cder/OPS/BCS _ guidance.htm US Food and Drug Administration, Center for Drug Evaluation and Research. The Biopharmaceutics Classification System (BCS) Guidance. Löbenberg R, Amidon GL: Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur. J. Pharm. Biopharm . ( 2000 ) 50 : 3 -20 . 9/25/2011