Lecture 2 “INFLUENCE OF PHARMACEUTICAL FACTORS, SUCH AS PHYSICAL STATE, SIMPLE CHEMICAL MODIFICATION OF MEDICINAL SUBSTANCE ON THE THERAPEUTIC EFFICIENCY OF MEDICINES ”

The maximal usage of «pharmaceutical factors» is the primary purpose of pharmaceutical technology for providing of high quality of medicines that coincides with the strategic task of biopharmaceutics which consists in the maximal increase efficiency of medications and decline to the minimum of possible side action on an organism. Therapeutic activity of medicinal substances caused by: constant factors (chemical structure, doze); variables factors (pharmaceutical).

Pharmaceutical factors and their classification PHARMACEUTIC AL FACTORS Physical state of medicinal substance Medicinal form and ways of application Auxiliary substances (their nature, physical state and quantity) Simple chemical updating of medicinal substance Technological process

Studying of pharmaceutical factors is obligatory from the point of view of biopharmaceutics in a view of their essential influence on dynamics of bioavailability of medicinal substances, stability of medicines during storage term and many other parameters. Pharmaceutical factors influence on: activity of substance; substance releasing from the medicinal form; absorption; distribution in organism; elimination. The physical state of medicinal substances influences on the stability of medicines during storage, therapeutic efficiency, speed of absorbtion, distributions and elimination from the organism.

On the biological action of medicines can influence and other factors: superficial properties of medicinal substance (hydrophilic or hydrophobic, etc.) a degree of cleanliness (a kind and quantity of impurity, a degree of cleanliness, presence of microorganisms or allergens) the nature of solvent presence of the environment, which protecting medicines from influence of acids and alkalis quality of packing storage term degree of crushing and polymorphism of medicinal substances influences on the pharmacotherapy most essentially

Polymorphs have different stabilities and may spontaneously convert from a metastable form (unstable form) to the stable form at a particular temperature. They also exhibit different: melting points, solubilities (which affect the dissolution rate of drug and consequently its bioavailability in the body), X-ray crystal and diffraction patterns. Various conditions in the crystallisation process is the main reason responsible for the development of different polymorphic forms. These conditions include: solvent effects (the packing of crystal may be different in polar and nonpolar solvents) certain impurities inhibiting growth pattern and favour the growth of a metastable polymorphs the level of supersaturation from which material is crystallised (in which generally the higher the concentration above the solubility, the more likelihood of metastable formation) temperature at which crystallisation is carried out geometry of covalent bonds (differences leading to conformational polymorphism) change in stirring conditions Despite the potential implications, polymorphism is not always well understood.

So, due to differences in solubility of polymorphs, one polymorph may be more active therapeutically than another polymorph of same drug: cortisone acetate exists in at least five different polymorphs, four of which are unstable in water and change to a stable form; carbamazepine (used in epilepsy and trigeminal neuralgia) beta- polymorph developed from solvent of high dielectric constant ex aliphatic alcohol, whereas alpha polymorph crystallized from solvents of low dielectric constant such as carbon tetrachloride; estrogen and chloroamphenicol also show polymorphism; resorcinol has two forms (  and  ); levomycetin stay in 4 polymorphic forms (А,В,С,D), but only B-form is an 100 % active; phenobarbital has 11 polymorphic forms; tetracycline – 4 forms; testosterone – 6 forms; prednisolon – 6 forms.

The physical state of medicine influence also on the therapeutic activity. Depending to this parameter all drugs are divided in 4 groups: dry (powders); liquid (solutions, suspensions, infusions, drops etc.); soft (ointments); gaseous (aerosols). According to the dispersive classification medicines are represented as all-round binary disperse system.

The solubility of substances depends on surface properties and their degree of crushing. Diferency of particles size of medicinal substances can cause to nonequal absorbtion rate and their content in biological liquids of the same medicine. So, the clinical non-equivalence is possible. All these should be taking into account while preparing of liquid medicinal forms for grounded a technological operations and composition of medicines. Surface properties are depends on: technological process of medicines obtaining; kind of medium; crystallization velocity; temperature of process; increasing of pressure; type of impurities etc.

Properties of the active pharmaceutical igredients (API) important to dissolution include: The solubility of the API in the dissolution medium, which is usually an aqueous buffer solution (may contain surfactants as well) Whether the API is hydrophilic or hydrophobic (ease of surface wetting) The particle size of the API Whether the API is crystalline or amorphous in the drug product If there are polymorphs, which polymorph is present If a salt form is used

Properties of the drug product important to dissolution include: Semi-permeable membrane Osmotic core containing drug Water Delivery orifice Drug solution Whether the product is designed to immediately release the API, to delay release, or to release the drug over time.

API properties Analytics In-Vitro Drug Release Formulation Design Formulation API properties Analytics Dissolution: An interplay of three groups of factors As a formulation design aid (since formulation can profoundly affect dissolution behaviour) As a quality control measure immediately after production for batch release As a quality control measure to check performance during the shelf life To predict performance under various dosing conditions („biorelevant“ methods) To verify that the quality of a product is not adversely affected when there is a change in excipients or manufacturing method (can sometimes be used instead of a pharmacokinetic study) To obtain approval for a multisource drug product („generic“ version of an existing drug product) – in certain cases a pharmacokinetic study is not required.

Dissolution as a quality control measure for batch release, and to ensure continued quality during the shelf-life. Here it is important to have a well-designed dissolution test that can detect batches with poor quality without rejecting batches of adequate quality. The USP and, recently, the International Pharmacopeia, make recommendations for specific drug products Standard dissolution method for highly soluble APIs –Paddle Apparatus –500 mL –SIFsp/IP Phosphate Buffer pH 6.8 (corresponds to one of the three pH values stipulated by the FDA in its biowaiver guidance) –75 Rpm –37 °C (corresponds to the temperature of the Gastro-Intestinal (GI) fluids; for transdermal products a lower temperature, usually 32°C is used, since this is closer to skin temperature) –Sampling at 30 min. –Specification: >85 % release within 30 min.

Therapeutical activity of medicinal substances depends on: Optical properties Among optical isomers there is no chemical distinction, but each of them revolves the plane of polarization ray in certain direction. In spite of the fact that the chemical analysis fully confirms the presence of the same substance in medicine with different isomers, they will not be therapeutically equivalent. Degree of ionization Depending on concentration of hydrogen ions the medicinal substances can be in the ionized or unionized form. pH index influences also on the solubility, coefficient of distributing of medicinal substances, membrane potential and superficial activity. Contain in molecul crystalline water The waterless medicinal substances and crystallohydrate has a different solubility that causes change of their pharmacological action. For example, the waterless forms of caffeine, ampicillin, teophylline dissolve quickly, as compared to their crystallohydrate and consequently is quickly sucked.

The clinical researches of application a simple chemical modification of medicines showed a differect results: For example: Chinin-base Chinin sulphate  solubility is 1 : 800 Chinin chloride  solubility is 1 : 34 Chinin bromide  solubility is 1 : 16 Tthese substances has a different pharmacokinetic (because a solubility is differ) but the activity is saved. For example: While glucose mix in medicinal form with following substances: Alkaline substances  the activity of euphylline, hexamethylentetramine, caffeine-sodium benzoate etc. dereased because the pH is changed; Cardiac glycosides  hydrolysis is carring out; Essenciale for injections  “muddy” is forming.

Simple chemical modification of medicines The same substance is represented as a different type of chemical compound (salt, base, esther, complex etc.), but the pharmacological activity is stable Simple chemical modification While replacing one substance by other we should be recalculate their amount in molecular mass or unit of action: For example: Replacing of medicines Medicinal substanceBase form Potassium bromide ()Sodium bromide () Codein phosphate ()Codein () Caffeine sodium benzoate ()Caffeine () Liquid phenol ( )Crystalline phenol ()

On the basis of biopharmaceutics researches proved that arbitrary replacement some ion in the molecule of medicinal substance, coming from cleanly technological or economic indicators is unpossible.