Pharmaceutical Incompatibilities: Causes, Types and Major ways of Overcoming in Extemporaneous Medicinal forms

Yarnykh T. G.¹, Kotvitska A. A.², Tykhonov A. I.³, Rukhmakova O. A.⁴*

¹Doctor of Pharmacy, Professor, Head of Drugs Technology Department, NUPh, Ukraine.

²Doctor of Pharmacy, Professor, Rector of NUPh, Ukraine.

³Doctor of Pharmacy, Professor, Professor of Cosmetology and Aromology Department, NUPh, Ukraine.

⁴Doctor of Pharmacy, Associate Professor, Associate Professor of Drugs Technology Department,

NUPh, Ukraine.

ABSTRACT:

The objective of the work – is to study and analyze causes of incompatibilities, their types and ways of overcoming in extemporaneous prescriptions based on data from literary sources. In the work, the retrospective, logical, and analytical research methods have been used to analyze the data of special literature. Based on the data of modern scientific literature, causes of pharmaceutical incompatibilities, their types and major ways of overcoming in extemporaneous prescriptions have been studied and analyzed. The given information of the problem of pharmaceutical incompatibilities, in our opinion, will increase the professional knowledge of pharmacists about the physical phenomena and chemical interactions that may occur in dosage forms, types of pharmacological incompatibilities and will guide them in practical activities in preparation of extemporaneous medicines in different dosage forms.

INTRODUCTION:

The concept of rational use of medicines is the subject of Good Pharmaceutical Practice (GPP). It involves the direct involvement of pharmacist in the process of pharmacotherapy, and provides for the responsibility of pharmacists for the use of medicines by the patient.

The pharmacist is responsible for identifying counterfeit/ improperly labeled drugs, ensuring the proper storage of drugs and the quality of their production, if necessary, and is responsible for the correct appointment and implementation of drug delivery, dosage, compliance of treatment regimens and dosage forms in each individual case. In addition, the professional duties of pharmacists include predictions and prevention of the interaction of drugs with other drugs and foods, the elimination of the possibility of occurrence of known and predictable side effects of drugs, minimizing unnecessary procedures, taking into account the cost of drugs.

The number of medicines has been increased in recent years. More than fifteen thousand manufactured medicines are used in medical practice. In spite of the variety of manufactured medicines, the extemporaneous prescriptions have not lost its value. Modern prescriptions are complex formulas (Dash et al. 2013; Tykhonov et al. 2016)^[2,16]. Thoroughly considered combination of some medicinal substances simultaneously often gives more expressed therapeutic effect than their individual using.

The formula itself can contain four-five and more ingredients, sometimes up to ten-fifteen. Prescribing a complex formula, in some cases the doctor stipulates for intensification of a specific effect of ingredients, the so-called pharmacological synergism, in other cases he intends to achieve weakening or removal of the side effect of one of the ingredients prescribed. To achieve the desirable therapeutic effect the phenomenon of antagonism (the opposite effect) of medicinal substances is also used.

Thus, a doctor should pay serious attention to compatibility of medicinal substances in the prescribed medicine (Tykhonov and Yarnykh 2016)^[17]. The character of interaction between medicinal substances depends on physical and chemical properties of these substances; dispersion medium; medicinal form; interaction of medicinal substances.

Pharmaceutical incompatibility is a combination of ingredients in which, because of the interaction of medicinal substances between themselves or with excipients, their physical and chemical properties change and thus the stability and effect of the medicine. In resolving the issue of compatibility of substances in the extemporaneous medicinal forms, it is necessary to take into account not only the therapeutic effect of the ingredients, but also their physical and chemical properties and the possibility of interaction (Rothschild et al. 2010)^[12]. There are two kinds of incompatibilities: “obvious ones” and “false ones”. A pharmacist cannot use formulas containing incompatible combinations of ingredients.

The objective of this work is to study and analyze causes of incompatibilities, their types and major ways of overcoming in extemporaneous prescriptions based on data from literary sources. In addition, we analyzed the structure of the pharmaceuticals standards as the main control and informational documents for the specialists of pharmacy establishments.

Depending on the character of changes, which can be formed when combining the ingredients in extemporaneous formulas the following incompatibilities can be distinguished: physical (physical and chemical) ones; chemical ones; pharmacological ones. The character of consequences, their degree of severity for a patient after preparation of medicines, which contain incompatible combinations, can be different: the therapeutic effect is reduced; the therapeutic effect is not achieved; the side effect is strengthened; they can lead to a lethal outcome.

Interactions that occur prior to taking medicines are called pharmaceutical incompatibilities, and the interactions that occur after taking medicines – pharmacological. Pharmaceutical incompatibilities are divided into physical and chemical depending on the nature of the changes that occur when a combination of medicinal substances (Kanji et al. 2010)^[6].

Physical incompatibilities are classified: insolubility of medicinal substances; immiscibility of ingredients; coagulation of colloidal solutions, solutions of high molecular compounds and emulsions; humidification and loss of wateriness in powders; adsorption of medicinal substances

Chemical incompatibilities are divided in accordance to: visual signs of reactions: formation of a precipitate; change in color, odor and gas release; changes occurring without external manifestations; type of reaction: oxidation-reduction, exchange, hydrolysis, substitution, decomposition, neutralization.

Physical incompatibilities are incompatibilities, in which there is a change in the physical state of medicinal substances. They can occur without external manifestations and manifest only in the reduction of the therapeutic effect (adsorption), and may be accompanied by chemical reactions (coagulation, evaporation of powders because of the neutralization reaction).

The insolubility of the medicinal substances is considered incompatible in cases where there is poisonous or strong-effective substances in the precipitate or if the coarse suspension or precipitate sticks to the walls, which makes the dosage precisely impossible. If the precipitate is not poisonous, it is easily resuspended and dispensed, so there is a pharmaceutical suspension, which is to be manufactured.

Immiscibility is observed when combining heterogeneous consistency of ingredients, hydrophobic and hydrophilic liquids. Occurs in liquid forms, ointments, pills and suppositories.

Coagulation of colloidal solutions, solutions of high molecular compounds and emulsions occurs under the influence of concentrated solutions of electrolytes, salts of heavy metals, acids, alkalis, alcohol, and syrups. In emulsions, coagulation of the protective colloid-emulsifier is also possible under the influence of temperature changes (Bentley et al. 2015)^[1].

It is possible to slow down the coagulation by pre-dissolving a coagulant in water; addition of a coagulant in portions with careful shaking; release of a coagulant with a dosage form.

Change of the consistency of the medicine is observed with the combination of zinc oxide and salicylic acid, when preparing gels on methylcellulose with resorcinol and iodine, when combined sodium carboxymethylcellulose with salts of heavy metals. Such processes are accompanied by a change in the dispersion of substances. To eliminate such incompatibility, the change in the type of dosage form or the selection of one of the components is used.

Dampening of powders is possible due to the adsorption of water vapor from the air or the separation of crystallization water. For example, pure sodium chloride is not hygroscopic, and if the content of a small admixture of salts of calcium or magnesium it is very quickly evaporated. When dampening of powders, in which the components of acid and alkaline are interconnected, there is an interaction between them (neutralization and oxidation reactions), and the physical incompatibility becomes physicochemical or chemical (Qiu et al. 2016)^[11].

Eutectics is a mixture that has a lower melting point than the original components, and is a solution that is saturated with both components. As a result, thick damp liquids are formed or the mixture breaks and loosens. Easily form eutectic mixtures of menthol, thymol, camphor, bromcamphor, antipyrin, chloral hydrate, phenyl salicylate and resorcinol. Eutectic can be prepared if its formation is provided by the doctor, for example, to receive dental drops.

Adsorption of medicinal substances is a concentration of a substance on the surface of a solid (adsorbent). It occurs under the influence of the molecular forces of the surface of the adsorbent and leads to a decrease in free surface energy. It can occur in powders, suspensions, pills, with the release of non-toxic precipitates in mixtures, which on their surface can adsorb medicinal substances. This is dangerous when the mixture contains poisonous or strong effective substances. Adsorbents can be dispersed substances, insoluble and non-absorbed in the gastrointestinal tract – activated carbon, calcium carbonate, aluminum hydroxide, talc, etc.

Chemical incompatibilities are incompatibilities, which are accompanied by unpredictable chemical reactions of prescribed medicinal substances. Because of chemical reactions, substances are formed inactive or poisonous. The nature of the interaction between substances depends on the physical and chemical properties of the substances, the type of dosage form, pH of the dispersion medium. The rate of reaction depends on the type of dosage form and temperature (thermal sterilization significantly accelerates the reaction, therefore, compatible combinations of substances may become incompatible) (Trissel 2013)^[15]. Formation of a precipitate leads to an incorrect dosage that is dangerous for precipitates, which are poisonous or strong effective substances. Therefore, such medicines cannot be dispensed.

Alkaloids and nitrogen precipitation occurs under the influence of alkaline reactants, barbiturates, salts of sulfanilamides, salts of heavy metals, iodine solution with potassium iodide, tannins. In the precipitate, hard-soluble salts of alkaloids fall. As an exception, do not form a precipitate quinine hydrochloride, morphine hydrochloride, codeine when combined with tannins.

Cardiac glycosides precipitation occurs when combined with heavy metal salts, tannins, salts of alkaloids and halogens. Cardiac glycosides are very sensitive to acids, alkalis and oxidants. They are partially or completely subjected to hydrolytic cleavage with the formation of poisonous precipitates, inactivation of glycosides occurs.

Precipitation of hard metals compounds occurs when they interact with tannins, cardiac glycosides, halogen compounds, alkaloids and nitrogenous bases, sodium salts of barbituric acid derivatives and sulfanilamide medicines. Precipitates can be formed because of exchange reactions between salts of heavy metals (Perez et al. 2015)^[9].

Precipitation of antibiotics occurs under the influence of acids, alkalis, some alcohols, salts of heavy metals. Even so weak organic acids, as ascorbic and salicylic, convert penicillin into inactive penicillinic acid, and mineral acids lead to deeper hydrolysis of the antibiotic. Alkaline substances reveal the lactam ring of penicillin and form physiologically inactive salts of penicillinic acid that do not have antibiotic activity. Salts of heavy metals (mercury, lead, etc.) inactivate penicillin due to the cleavage of the thiazolidine ring and, in addition, form poorly soluble compounds with antibiotics.

Change in color, smell and detection of gases indicates deep chemical transformations of their components with a loss of therapeutic activity. The indicated manifestations can be observed because of reactions of displacement of weak acids and alkalis by stronger, recovery reactions, and the like.

Weak acids, from which salts can be released gases, is nitrite, thiosulfate and carbonate. In the interaction of these salts with stronger acids, respectively, nitrogen oxides, sulfur dioxide or carbon are formed. Hydrogen peroxide oxidizes phenols, destroys in the presence of alkalis. Ammonia salts under the influence of alkalis can emit gaseous substances. In alkaline medium, it is possible to observe the decomposition of chloral hydrate to form chloroform, which is felt by the smell (Newton 2009)^[8].

Changes that occur without visible signs can occur because of chemical reactions and lead to the formation of inactive or toxic products. Hydrolysis is observed in combination with cardiac glycosides with acids. Nourishing agents hydrolyze cardiac glycosides to a lesser extent. Neutralization of antibiotics occurs when the pH is reduced or increased. Thus, streptomycin sulfate in aqueous solutions is more stable at pH 3-7, and in an alkaline environment, it is easily inactivated. It is deposited with alkaloid reagents, dyes, and is easily oxidized. Redox processes occur between substances with significant oxidation and renewable properties. Often oxidation-reduction processes are observed in liquid dosage forms, less frequently in ointments, powders, suppositories and pills (Elliott and Liu 2010) ^[3].

Pharmacological incompatibilities are a combination of substances, which in some cases leads to a decrease or complete loss of therapeutic effect, in others – to increase its toxicity or manifestation of adverse side effects. Pharmacological action is manifested in the form of synergism and antagonism.

Antagonism: lobelin and morphine – lobelin excites respiratory centers, and morphine depresses them; strychnine and chloral hydrate – strychnine excites the motor division of the nervous system, and chloral hydrate – suppresses and paralyzes it; K⁺ and Ca⁺⁺ ions used in the form of soluble salts – K⁺ ions inhibit cardiac activity, slow down the allocation of glucose by the kidneys, stimulate smooth muscle, and Ca⁺⁺ ions, on the contrary, increase cardiac activity, increase glucose secretion and relax smooth muscle, etc. (USP Pharmacists’ Pharmacopeia 2008)^[13].

Sinergoantagonism (partial antagonism) is observed when the medicinal substances are synergistic in some effects and antagonistic in others. For example, in the treatment of acute pneumonia with streptomycin and ascorbic acid, the toxicity of the antibiotic is significantly reduced and the dynamics of X-ray, laboratory and clinical parameters is improved. Similar results are observed when combining antituberculous medicines with pyridine-containing vitamins: nicotinic acid and pyridoxine (Klopotowska et al. 2010; USP Pharmacists’ Pharmacopeia 2008)^[7,10].

For the searching the solvencies of such problems as incompatible combinations of medicinal products also the object is the joint WHO and FIP guidance “Appropriate Pharmacy Practice: Quality Standards for Pharmacy Services”, guidelines for pharmaceutical practices from different countries of the world. The analytical-comparative method, as well as analogies and generalizations, is used. This article does not contain any studies with human and animal subjects performed by any of the authors.

For the first time, the document, which became the basis for the development of national standards for GPP, thee was developed by the International Pharmaceutical Federation and was adopted at a consultative meeting in Tokyo in 1993 and updated in 1997. The FIP/WHO Public Pharmacy Practices document was published in the thirty-fifth report of the WHO Expert Committee on Pharmaceutical Specifications in 1999, and was re-updated in 2011, taking into account the ongoing changes taking place in the pharmaceutical market through consultations with 120 national FIP members (World Health Organization 2011; Reference guide on GPP in community and hospital settings 2009)^[4,5].

Today, a number of international organizations, such as the World Health Organization (WHO), the International Pharmaceutical Federation (FIP) and the European Directorate for Quality of Medicines (EDQM), are involved in the development of recommendations for GPP standards. The recommended guidance adopted by WHO and the FIP defines GPP as a pharmacy practice that meets the needs of people who use the services of pharmacists in providing optimal care based on evidence-based medicine. Document states that it is necessary to create strategies for the implementation of national GPP standards.

GPP's goal is to promote health and help people with health problems through the rational use of medicines. At the same time, pharmacists, together with other representatives of the health system and patients, should take responsibility for the results of treatment. The document sets the framework within which each country has to propose its national standards for providing population with quality drugs and related products, pharmacy assortment, professional advice and information. First and foremost, basic pharmaceutical services for which the regulatory framework has to be developed, and relevant standards.

In Ukraine, Pharmacy Practice is approved: Pharmacy Quality Standards (approved by the Ministry of Health of Ukraine № 455 dated May 30, 2013)[14]. GPP defines the functions, roles and activities of pharmaceutical workers, including their responsibilities. In particular, the document identifies 4 roles and 15 functions for pharmaceutical workers as presented in Table 1.

Table 1: Types of activities of pharmaceutical workers according to Good Pharmacy Practice: Quality Standards for Pharmacy Services

It should be noted that roles can vary for each pharmacist depending on the responsibilities they perform and specific GPP standards can only be developed within the framework of national professional pharmacy organizations (The Order of the Ministry of Health of Ukraine № 455, 2013)[14].

According to GPP data, in order to perform the function of manufacturing extemporal drugs, the pharmacist should ensure that the preparation of extemporal drugs will prevent the incompatibility of the drug, eliminate the possibility of occurrence of known and predictable side effects of drugs, minimize the possibility of error in the administration of drugs, ensure the purity and safety of medicines.

Thus, according to the results of the study, it can be argued that the role and functions of the pharmaceutical worker is expanding, as well as the need to consider the problem of pharmaceutical incompatibility. Solving this problem will enable to increase the professional knowledge of pharmacists about physical phenomena and chemical interactions that may arise in medicinal forms, types of pharmacological incompatibility and direct them to practical activities in the preparation of extemporal drugs in various forms.

Further, based on data from literary sources, we analyzed the causes of incompatibility, their types and the main ways to overcome the errors in extemporal recipes. One of the examples of physical (physicochemical) incompatibilities is immiscibility of ingredients, hydrophobic and hydrophilic liquids. Data on the mutual mixing of some liquids is given in Table 2.

Table 2: mixing of separate liquids

Another example of this type of incompatibilities is loss of fluidity in powders (Table 3). It may occur immediately or after a short time after preparation. The reactions in powders continue, as a rule, long and fully detected during storage.

Table 3: Some examples of incompatibilities of medicinal substances in powders

Ascorbic acid

Hexamethylenetetramine, dimedrol, iron lactate, calcium gluconate, nicotinic acid, caffeine sodium benzoate, sodium bicarbonate, sodium nitrite, sodium phosphate, proserin 

Dampening, yellowing

Pancreatin

Inactivation of pancreatin

Oxidizers

Oxidation, inactivation

Calcium gluconate

Ascorbic acid

Dampening 

Camphor

Anestesin, acetylsalicylic acid, menthol, sodium salicylate, sodium phosphate, resorcinol, phenyl salicylate, phenol

Creation of eutectics

Strong oxidizing agents

Decomposition

Novocain

Silver nitrate

Mutual decomposition 

Papaverine hydrochloride

Adsorbents

Adsorption

Potassium permanganate

Salicylic acid

Antipyrine, bromcamphor, menthol, sodium salicylate, sodium tetraborate, sodium phosphate, pyrogalol, resorcinol, lead acetate, thymol, phenyl salicylate, phenol

Loss of fluidity

Vitamins exhibit high reactivity both with each other and with other medicines (pharmacological incompatibilities) (Table 4).

For fat-soluble vitamins, it is necessary to take into account their light oxygen oxidation with oxygen. Water-soluble vitamins B₁ (thiamine chloride and bromide) are destroyed in alkalis and neutral solutions, and inactivated under the influence of oxidizing agents and reducing agents. Riboflavin (B₂) in a neutral medium is a weak oxidant and a potent reducing agent.

When heated solution of riboflavin (at pH 7.2-7.9) for an hour its activity decreases by 50 %. It is the most stable in solutions at pH 5.0. In aqueous solutions (especially in light) accelerates the oxidation of ascorbic and folic acid, thiamine.

Table 4: Incompatibility of vitamins

В6, В12 (when injected in one syringe)

Е, В15 (folic acid)

В12, В15 (folic acid), Е

Responsibility of a pharmacist and ways to complete incompatibilities in prescriptions

A medicine, in which physical or chemical changes are possible, cannot be released (USP Pharmacists’ Pharmacopeia 2008) ^{[10, 13]}. When preparing medicines, a pharmacist should apply all necessary measures to prevent or eliminate the incompatibility of the ingredients. For a qualitative solution to this question, a pharmacist must constantly study the reference literature, manufacturers' information on the properties of medicines, in order to predict the possibility of their interaction.

There is no universal way to overcome incompatibilities in medicines. In each case, a pharmacist can find ways and means to solve the problem, based on knowledge of the physical and chemical properties of the components. For example, using the following techniques:

1.     Drying of crystalline hydrates is recommended for the preparation of powders in order to remove crystalline water. 2. Fractional mixing is recommended to reduce the contact between the ingredients in the preparation of dosage forms. 3. Introduction of auxiliary substances - moisture regulators is recommended for the adsorption of moisture in mixtures, where the chemical interaction of the components is possible. The quantity and type of the regulator are selected experimentally, taking into account the compatibility of the ingredients.

      To overcome incompatibilities, it is also possible to use the following methods, but such changes should be necessarily agreed with the doctor who prescribed the prescription.

2. Replacement of medicinal substances and change of solvent. Reasonable is the replacement of the following substances: potassium bromide – sodium bromide, codeine – codeine phosphate, sodium caffeine benzoate – caffeine, sodium tetraborate – boric acid, euphylline – theophylline. If medicinal substances are insoluble in the prescribed solvents, partial or total replacement of the solvent is possible

3.   Replacement of the dosage form. A mixture of camphor with phenyl salicylate or chloral hydrate is not compatible in powders, but are compatible in the pills and in the liquid form – dental drops.

4.   Isolation of one of the components of the medicine. In the implementation of this method, it is prohibited to release poisonous, narcotic and strong effective medicinal substances out of the composition of the medicine. Isolation of one of the components of the prescription is also recommended when combined in one form of alkaloids, enzymes, antibiotics, glycosides or other medicinal substances with adsorbents. If it is necessary to introduce a form-forming component, then another filler, for example, sugar, sodium bicarbonate, is used. In each of the last three cases, you need to get a new prescription from a doctor.

CONCLUSION:

According to the results of the analysis of GPP data, it has been established that the duties of pharmaceutical workers include the manufacture of extemporal drugs, which involves preventing the pharmaceutical incompatibility, eliminating the possibility of occurrence of known and predictable side effects of the drug. Causes of pharmaceutical incompatibilities, their types and major ways of overcoming in extemporaneous prescriptions based on data from literary sources have been studied and analyzed. The given information of the problem of pharmaceutical incompatibilities, in our opinion, will increase the professional knowledge of pharmacists about the physical phenomena and chemical interactions that may occur in dosage forms, types of pharmacological incompatibilities and will guide them in practical activities in preparation of extemporaneous medicines in different dosage forms.

AUTHORS’ CONTRIBUTIONS:

All authors have made substantial contributions to the work reported in the manuscript.

CONFLICTS OF INTEREST:

All the authors hereby declare that there are no conflicts of interest.

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Received on 10.07.2019           Modified on 12.09.2019

Accepted on 05.10.2019         © RJPT All right reserved