Chapter 4 Incompatibility
Medicinal substances. Physical and physical and chemical
Incompatibility. Chemical incompatibility.
Incompatibility of medicinal substances.
Incompatibility of medical products - easing, loss or
A distortion of medical effect of medical products or amplification
Their collateral or toxic action.
Such combination is called as pharmaceutical incompatibility
Components, at which as a result of interaction
Medicinal substances among themselves or with auxiliary
Substances essentially change their physical and chemical
Properties, and thus and therapeutic action. These change,
Not stipulated by the doctor, can occur in process
Manufacturing and storage of medical products.
The change, occuring at joint application medicinal
Means, carry to pharmacological incompatibility and
Consider in a rate of pharmacology.
Pharmaceutical incompatibility on character of processes, her
Causing, divide into 2 groups:
à) physical or physical and chemical incompatibility;
á) chemical incompatibility.
This division is conditional, in one preparation can be combined
Various kinds of incompatibility.
Pharmaceutical incompatibility
Irrational combinations incompatible combinations
(easing or loss of medical properties) (amplification collateral
Or toxic action)
The doctrine about universality and omnipotence of pharmacotherapy (polypharmacy)
Has received development last decade B.C.
Medical products, characteristic for this epoch, had
Complex structure (terlaki - up to 70 components). In such complex
Mixes could be and incompatible components.
In days of Galena (II century AD) struggle with excessive was conducted
Complexity of recipes. Principles of simplicity and complexity of structure
Medical products alternated during all history
Medicine and pharmacy.
During one hospitalization of the patient receives on the average 8-14
Various preparations, the majority from which is a lot of components.
More than 20 % of medicinal complications are connected to interaction
Preparations during polytherapy.
A problem of prevention of pharmaceutical incompatibility
Is a part of the general problem of stabilization medicinal
Preparations. The basic ways of prevention of incompatibility:
à) use of technological receptions without change of structure
propisi;
á) introduction in propisi a medical product auxiliary
Substances or change of structure propisi;
â) to replacement of some medicinal substances;
ã) replacement of the medicinal form.
à) This way is reduced to the certain sequence
Dissolution (mixture) of components of a complex preparation.
For example, the certain sequence of dissolution
Components it is recommended at manufacturing mixtures, in structure
Which salts alkaloidov or synthetic, nitrogenous enter
The bases (salt of the weak bases and strong acids) in a combination with
Substances with alkaline reaction of environment. In some cases
It is possible to avoid settling out of the bases alkaloidov, if
Other components to add as solutions in the order
Increase their value rN.
Separate dissolution of medicinal substances regarding
Solvent, separate their mixture with a part of a basis or other.
Components of a preparation and the subsequent association of parts
Are applied to prevention of incompatibility in powders,
Liquid preparations for internal and external application, ointments,
suppozitorijah, solutions for injections, eye drops, etc. LF.
á) the Most part of cases of incompatibility prevent by
Applications of various auxiliary substances in quality
Solvents, stabilizers emulsy, antioxidants, substances,
Regulating value rN, absorbers of a moisture, mazevyh bases and
Etc.
â) Overcoming of incompatibility by replacement: ÊÂr →NaBr; kodein →
kodeina phosphate; caffeine →áåíçîàò sodium → caffeine; sodium
tetraborat → an acid boric; phenol liquid → phenol
Crystal; eufillin → teofillin.
ã) Overcoming of incompatibility by replacement of mixtures with powders;
Drops on mixtures; powders on mixtures.
Physical and physical and chemical incompatibility.
Principal causes:
Insolubility of medicinal substances; nesmeshivaemost
Components; coagulation kolloidnyh systems; otsyrevanie and
Fusion of complex powders; adsorption of medicinal substances.
Insolubility of medicinal substances.
Insolubility of medicinal substances in liquid environments
Consider as incompatibility in the following cases:
In a deposit there are poisonous or strong substances;
At manufacturing are formed grubodispersnaja a suspension or a deposit,
Which sticks to walls and a bottom of a bottle and prevents exact
To batching a preparation.
Examples of insolubility of medicinal substances in water, ethanol,
Glycerin, oil.
à) caffeine caffeine and amidopirin dissolve in hot water. At
Cooling
amidopirin a solution the deposit of caffeine, since it decreases
Solubility in in
NaBr de - 1 : 80. It is recommended: instead of caffeine to take caffeine-áåíçîàò
Water distilled sodium
á) oil kastorovoe oil kastorovoe is not dissolved in 70 %
Ethanol. It is recommended: to take
70 % ethanol of 90 % ethanol.
â) benzocaine benzocaine is not dissolved in glycerin.
Sodium tetraborat It is recommended: the part of glycerin will replace
Ethanol in which to dissolve
Glycerin benzocaine.
ã) phenol liquid phenol liquid is not dissolved in fat oils.
Oil peach Is recommended: replacement of liquid phenol
Crystal.
Nesmeshivaemost components.
Nesmeshivaemost components can cause incompatibility
Substances, diverse on a consistence, a modular status, at
A combination of waterproof substances, for example fat oils, liquid
Paraffin, tar with water solutions, ethanol, glycerin, etc.
Liquids. (Ether), necessary for dissolution of a part specified
Liquids (water); Paraffin liquid mixs up in all parities
With vegetable oils, except for kastorovogo.
Coagulation kolloidnyh mixes.
Many galenovye preparations are combined disperse
istemami. At infringement of sequence of manufacturing complex
Mixtures ekstraktivnye substances can koagulirovat. Coagulation
kolloidnyh systems occurs under influence concentrated
Solutions of electrolits, ethanol, etc. vodootnimajushchih substances.
Solutions kollargola, protargola and ihtiola often are incompatible with
Salts of mineral acids, salts alkaloidov or synthetic
The bases.
Otsyrevanie and fusion of complex powders.
Otsyrevanie and loss of flowability of complex powders are caused
Two principal causes:
Hygroscopicity of a mix of substances usually is more than hygroscopicity
Components making her;
Allocation of water as a result of chemical reaction.
Examples:
à) a Dimedrol if in zatertoj glucose to a mortar to pound a Dimedrol,
Sodium gidro-
Sodium a hydrocarbonate a carbonate and glucose, weight of a dampener
Through 10-15 '.
Glucose is recommended: a Dimedrol to pound with glucose, and then
Cautiously
To mix from sodium a hydrocarbonate. In this case powders
Save
Flowability within 3-4 day.
á) an acid atsetilsalitsilovaja after a while a mix
Is humidified, sticks together and issues
amidopirin a smell of a vinegary acid. Goes r-ja between an acid.
Caffeine - benzoat sodium
Atsetilsalits. And amidopirin → amidopirina salitsilat + vinegary
An acid. The vinegary acid humidifies a mix and because of
Hygroscopicities absorbs a moisture and accelerates reaction. Amidopirina
salitsilat on light decays and paints a mix in yellow color.
Speed of reaction depends on a parity amidopirina and acids
atsetilsalitsilovoj (their interaction is the fastest at
ekvimoljarnom a parity).
Many complex powders, in which structure can dampen
Enters eufillin (double salt teofillina with etilendiaminom). He
gigroskopichen and at a combination to the substances having sour
Character, enters with them interaction. Mixes thus
Blur and often turn yellow. Eufillin it is incompatible with an acid
Ascorbic, salts of the weak bases and strong acids-
A Dimedrol, dibazolom, spazmolitinom, etc.
For prevention otsyrevanija powders with eufillinom it is offered
To add in them of 3-5 % aeroforce. Protective action aeroforce
It is caused by a mechanical obstacle to interaction reacting
Particles and absorption aerosilom a moisture formed in process
Interactions of components of a mix.
Adsorption of medicinal substances.
Adsorption - to concentrate substances from volume of phases on
Interfaces between them (for example, gas → a solution) on
Surfaces of a firm body (adsorbenta). Adsorption is applied in
Pharmaceutical technology for water treating, vaseline, glucose,
Extraction from vegetative raw material.
Adsorbtsionnymi properties activated coal possesses,
bentonit, clay white, calcium a carbonate, aluminium gidroksid,
Talc, starch.
Chemical incompatibility.
The basic kinds:
Reactions of education insoluble and malorastvorimyh connections;
Hydrolysis of organic substances, education of gases; oxidations and
Restoration.
1. Education of deposits.
The reason of education of deposits in liquid LF can be various
Chemical processes (reak-
tsii neutralizations, an exchange, oxidation-reduction).
Many medicinal substances entering reactions with
Education of deposits, concern to salts of the weak bases and
Strong acids, to salts of the strong bases and weak acids, and also
To connections heavy and shchelochnozemelnyh metals.
Salts of the weak bases and strong acids - are steady only in sour
To environment. In the alkaline environment many weak bases it is not enough rastvorimy
Also drop out in a deposit. Are especially sensitive to the alkaline environment
Salts morfina, atropine, papaverina, a Dimedrol, dibazol.
Salts of the strong bases and weak acids - caffeine - benzoat of sodium,
Sodium tiosulfat, sodium nitrite, sulfatsil-sodium are unstable in
To the sour environment and consequently are stabilized sodium gidroksidom or
Sodium a hydrocarbonate. At interaction with acids can
To decay with allocation of a deposit also natrievye salts
barbiturovoj acids, norsulfazol-sodium, sodium benzoat,
Sodium salitsilat, eufillin.
Connections of heavy metals (aluminium, mercury, silver, lead,
Zinc). They can form deposits with tannins,
Intimate glikozidami, connections of halogens, alkaloidami,
The nitrogenous bases, natrievymi salts of derivatives
barbiturovoj acids and sulfanilamidnyh preparations. To group
shchelochnozemelnyh metals chloride concerns calcium. He
It is incompatible with carbonates, salitsilatami, sulfates, phosphates
(can reduce are insoluble or difficultly soluble salts
Calcium); with salts of lead, silver (can be formed
Insoluble chlorides); with barbitalom sodium - malorastvorimaja
kaltsievaja salt barbitala.
2. Hydrolysis of organic substances.
Under influence of sodium of a hydrocarbonate and drops nashatyrno-anisic
Are hydrolized intimate glikozidy from nastoja herbs of an adonis.
Benzilpenitsillina kalievaja salt is a derivative tiazolidina,
Containing very unstable β - laktamnoe a ring. This ring
It is easily hydrolized under action of acids, alkalis, enzyme
penitsillinazy, etc. substances. Benzilpenitsillin collapses also
At a combination to oxidizers, salts of heavy metals, ethanol.
In liquid LF BP it is incompatible with glycerin, naphthalene, rezortsinom,
Zinc oksidom, tiaminom, adrenaline a hydrochloride, efidrina
A hydrochloride, iodine, jodidami.
3. Allocation of gases.
At combinations:
Salt of a weak flying acid with rather strong acid;
Salt of the weak flying basis with rather strong
The basis; when between substances proceed about-â reactions.
Weak acids from which salts gases can be allocated,
Are nitrogenous, tiosernaja and coal. At interaction
These salts with stronger acids are formed oksidy nitrogen,
dioksidy sulfur and carbon.
At combination Na2S2O3 with ÍÑI are allocated sulfur dioksid and free
It is grey.
Na2S2O3 +2HCI →2NaCI + SO2↑ + S↓
60 % r-r 6 % r-r
Treatment of an itch is based on this reaction. Carbonates Sa and Νà
Are incompatible with stronger acids, than coal:
ÑàÑÎ3 + 2ÍÑI → ÑàÑI2 + Í2Î + ÑÎ2
Hydrogen peroksid it is unstable in the alkaline environment (decays with
Allocation of oxygen):
2 Í2Î2 → 2Í2Î + Î2↑
Therefore he is incompatible with alkalis, carbonates, boratami,
Having alkaline reaction of environment. The weak bases, from salts
Which can be allocated under influence of alkalis gaseous
Substances, ammonia and his connection with formaldehyde is-
geksametilentetramin. Geksametilentetramin decays with
Allocation of formaldehyde.
4. Oxidation-reduction reactions.
ÊÌnO4 it is incompatible with the majority organic medicinal
Substances. In sour
environment
It is restored Ìn7 + → Mn2 + in the neutral and alkaline environment
Ìn7 + restore up to Ìn4 +.
ÊìnO4, being a strong oxidizer, it is incompatible from sodium
Nitrate (oxidation in nitrate), a hydrochloric acid and its salts
(education of free chlorine), bromides (oxidation up to
Free bromine), jodidami (allocation of free iodine),
Hydrogen peroksidom (allocation of oxygen in the sour environment). He
Oxidizes ethanol in aldehyde vinegary and a vinegary acid, glycerin
- in a mix ant, propionovoj, tartronovoj and coal
Acids. At grinding ÊìnÎ4 with sulfur, glycerin, ethanol,
Tannin, oils, the sugar activated by coal, etc.
Organic substances can take place even explosion.
Phenols (phenol, rezortsin) and the substances having easily are oxidized
Phenolic groups (adrenaline, sodium salitsilat, tannin, morfin and
Other).
Incompatibility of an acid ascorbic it is caused by its properties
A strong reducer. She is oxidized iodine, tsiankobalaminom,
An acid folic, etc. The Acid ascorbic nesovmestimas
geksametilentetraminom (decomposition GMTA on formaldehyde and
Ammonia), carbonates (decomposition with allocation ÑÎ2), benzoatami and
salitsilatami (sedimentation t/r benzojnoj and salicylic acids),
Salts barbituratov and sulfonamidov (sedimentation n/r barbituratov
And s-a).
Tiamin (vitamin Â1) is incompatible in neutral and alkaline
Solutions with oxidizers (nikotinamid and a nicotinic acid).
Decays reducers (glucose, sodium sulphite).
TSianokobalamin (vitamin Â2) is incompatible with oxidizers (Í2Î2,
ÊìnO4, etc.), reducers (sodium bisulphite, tsistein and
Other), with heavy metals.
Easily are oxidized also retinol (vitamin À), riboflavin (vitamin
Â2), tocopherol acetate (vitamin E acetate).
Easily are oxidized amidopirin, analginum.
At oxidation amidopirina are formed inactive painted in
Blue-violet color of connection.
An example of the modern approach to the prevention of incompatibility
Stabilization of the powders containing an acid is
atsetilsalitsilovuju, a Dimedrol, an acid ascorbic and calcium
laktat ("Antigrippin"). As a result of interaction of an acid
Ascorbic with a Dimedrol and calcium laktatom powders at
Storage dampen and change painting. At addition aeroforce
Powders are suitable for application within 2 months. In the way
Separate granulirovanija acids ascorbic and the others
Components it was possible to prolong working life "Antigrippina" in
To the form of tablets till 1 year.
For overcoming pharmaceutical incompatibility it is necessary
To develop new ways of their overcoming, to use more
Effective stabilizers, emulgatory, solvents,
Extra packings, etc.
