Interactions and incompatibilities in pharmaceutical preparations University of Pécs Institute of Pharmaceutical Technology and Biopharmacy
Medicinal interactions Processes which influence the medicines: absorption, distribution, metabolism, excretion. Administering two or more medicines (with the same or adverse effect) simoultanously causing alterations in the effect.
In vivo interactions Pharmacological or therapeutical interactions Synergism Increased drug effectiveness, as the combined effect is greater than the sum of each drug acting independently. Antagonism Decreased drug effectiveness, as the combined effect of two or more agents is less than the sum of each drug acting alone. New effect An effect that neither drug shows on its own (e.g. toxicity).
Technological interaction - are interactions between the constituents of the preparation, which can be derived from the: - composition of the medicine - method of preparation of the medicine Interactions can occur between the: -API(s) -excipient(s) -primary container
Technological interaction Intended (advantageous) Unintended (disadvantageous)
Unintended interaction = incompatibility Unintended chemical physical physicochemical colloidical microbiological changes, which influence the character and the efficacy of the medicine adversely.
Appearence of the incompatibility 1. Visible (macroscopical) 2. Masked (hidden)
Chemical incompatibilities Physical incompatibilities
Chemical incompatibilities a) Reaction between the constituents, b) Oxydation, c) Hydrolysis, d) Polimerisation, e) Esther formation, f) Formation of complex bonds, g) Formation of new salts, h) Spatial rearrangements.
Physical incompatibilities Adhesion, adsorption, absorption Mechanical inclusions (crystal inclusion) Formation of micelles (solubilisation) Decrease in solubility Loss of water Liquifying Formation of physical complexes
Physicochemical incompatibilities Adverse charge of initial substances
Colloidical incompatibilities Coagulation of droplets Change in viscosity Cementation/caking of the sediment Increase in particle size Chage in consistency
A few incompatibilities: Insoluble API in a vehicle Presence of immiscible constituents (oil & water) Appearence of precipitation Dehydration (mucilages and electrolytes) Cementation (caking) of substances in liquid dosage forms Decrease in solubility during the preparation (ie. Tinctura aurantii and water)
A few incompatibilities: Gas formation Coloration Liquifying of solid dosage form (change in aggregate condition) (pl. camphora and menthol)
Avoiding liquifying Avoiding formation of eutectic system: -application of small particles, which covers the surface of the reacting substances, therefore avoids the physical contact. i.e.: MgO, Al 2 O 3, Kaolinum ponderosum, Silica colloidalis hydrica
Change in consistency: softening Emulgents usually alter the consistency of ointments. Hygroscopic substances can also cause softening (NaBr, CaCl 2 ) in solid dosage forms.
Change in consistency: hardening Application of liquid fatty acids together with ZnO modifies the soft structure of the ointment. The same phenomenon can be observed at boric acid and ZnO.
Masked incompatibilities (hidden) 1. Part of chemical reactions occuring in the medicines are invisible macroscopically ie.: Acetyl salicylic acid reacts with polyethylene glycol Ascorbic acid decomposes in the presence of oxydizing agents 2. Phenomenon of adsorption (bentonit, Aerosil, kaolinum ponderosum)
Incompatibility of the container Metallic tubes: Mercury containing substances can interact with the steel tubes. Plastic: Adsorption on the plastic surfaces. Deformation of the container by interaction of polyoxethene and PVC.
Guidelines for the preparation of medicines avoiding incompatibilities Incompatibility can only occur in cases when the doctor prescribes a magistral preparation neglecting the guidelines of the pharmacopoea or the national formulary (standardised prescriptions). In all cases the quality, safety and the efficacy of the preparation has to comply the rules of the pharmacopoea, therefore the formula (composition) has to be altered according to the guidelines. Remember! Alterations should only be made if it does not influence the effect of the medicine adversely!
Cause of the incompatibility Finding the cause Elimination of the cause by hindering the incompatibility with a modified preparation or addition of extra substance
SOLUTIONS Alkalic or acidic medicines should be neutralized or adjusted to the proper ph value Adjusting the ph - by HCl or NaHCO 3 Substance can be changed if a soluble form (salt) is available in the proper vehicle taking into account the molecular weight. In these cases the dosing should be equal. Proper solvent can be used in the least quantity (max 5%) as the part of the vehicle to enhance the solubility of the substance. In these cases the amount of the vehicle should be less by the amount of the extra solvent. If none of the methods mentioned above can be used, emulsion of suspensions should be made. Or! The incompatible substances should be prepared separately in the original dosage form in two containers!
Rp. Papaverinii chlorati g 0,50 Phenobarbitali natrici g 0,20 Aquae destillatae ad g 20,0 MDS: Take 10 drops 3-times a day. According to the amount of APIs either alkalic or acidic ph will be dominant. At alkalic ph phenobarbital precipitate forms, at acidic or neutral ph papaverine precipitate forms. Avoiding incompatibility can be carried out in three ways: Adjusting ph with tartaric acid (application of 50% amount of papaverine) Preparation of suspension (adding mucilages and changing the phenobarbital sodium to phenobarbital) Preparation in two containers separating the APIs.
Rp. Argenti proteinici g 0,15 Ephedrinii chlorati g 0,05 Aquae destillatae ad g 10,0 MDS: Nose drops Colloid silver decomposes in the presence of electrolyte, therefore the APIs should be separated in two containers: they should be both dissolved in 10-10g water and applied after 30 min pause.
SOLID DOSAGE FORMS (POWDERS) Liquifying of powders can be caused by 1. Depression in melting point 2. Increase in hygroscopicity 3. Liberation of crystal water 4. Chemical changes
Chemical incompatibility Pulvis combinatus FoNo VII. (Pulv. combinat.) Coffeinum 0,50 g Noraminophenazonum natrium mesylicum 3,50 g Acidum acetylsalicylicum 3,50 g Acidum silicicum colloidale hydrophylum 0,50 g 10 pieces of divided powders
Effect of humidity or water Rp. Phenolphtaleini g 10,0 Natrii bicarbonici g 100,0
Effect of temperature (heat) Dilution of acids Silver nitrate and iodophorm dry mixture is an explosive composition
Loss of crystal water Na 2 SO 4 10 H 2 O + MgSO 4 7 H 2 O = Na 2 SO 4. 4 H 2 O + 13H 2 O This change only occurs at a definite weight ratio: Na 2 SO 4 (57%), MgSO 4 (43%.)
Preservatives Phenols, carboxyl acids has ability to create hydrogen bonds with polysorbate s ethylene-oxide group.
PARENTERAL NUTRITION all in one infusions - stability of fatty emulsions droplet size, which is mainly influenced by the presence of electrolytes and the ph. The incompatibility can occur in two steps: Flocculation, then skimmering (reversible) Coalescence (irreversible phase separation) Lipid emulsions containing MCT+LCT are more stable, than standalone LCT emulsions. Mixing of different lipid emulsions is not suggested!
PARENTERAL NUTRITION Electrokinetic potential Cations can bind on the surface electrostatically. If the electrolyte concentration increases, the surface charge and the zeta-potential is near zero. At this critical point the flocculation starts. ph of the nutritive mixture influences the surface charge of the fatty droplets, which is neutral at ph 3.0. (Glucose solutions decrease the ph of the mixture, thus causing the flocculation of the drops.) Temperature High temperature is well tolerated, but the freezing decomposes them. In mixtures heat stability is lower and tolerance against cold is higher.
PARENTERAL NUTRITION Aminoacids stabilize the lipid emulsions. They are able to protect against the flocculisation caused by electrolytes. This is due to their buffer effect and the formation of ligands with metallic ions.
PARENTERAL NUTRITION There might be several interactions between the TPN emulsions and vitamins. According to the general rule, vitamins should be added immediately before the administration of the infusion. Infusions containing vitamin A, E and C also need light protection.
PARENTERAL NUTRITION Calcium and phosphate content is critical regarding the precipitation. Formation of calcium-phosphate precipitate can be facilitated by the heat, the increasing ph, decreasing aminoacid content, the duration of the storage and if the calcium is added before the phosphate into the infusion.
SUMMARY Recognizing the possible incompatibility Exploring the causes Possible macroscopic or hidden manifestations Avoiding the incompatibility
Thank you for your attention!