Most examples of in vitro drug instability arises from oxidation and hydrolysis12. However, terbinafine does not contain any phenols or polyunsaturated compounds (which are susceptible to oxidation, if present), nor does it contain any esters or amides (which are susceptible to hydrolysis, if present)12. Thus, it can be assumed that under normal in vitro conditions, or on the shelf, terbinafine should be relatively stable. However, oxidation of the tertiary butyl group is undergone in the liver6, so if the in vitro conditions are similar to that of the liver, chemical stability will be compromised. In an experiment of terbinafine HCl tablets and creams, at six month accelerated storage at 40±10C, chromatograms showed that there is no degradation, indicating that these forms are quite stable13. However, a chromatogram of the solution form of terbinafine HCl stored under the same conditions indicated hydrolytic degradation, with 4 degradation products indicated by 4 significantly different RF values13.
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E: Stereochemical Properties (1)
Terbinafine has no stereocenters, since its sp3 hybridized carbons all have two or more of the same atom attached to them individually1. Its alkene functional group is mainly in the E configuration because it is more stable than the Z configuration3.
F: Intermolecular Forces (1)
The nitrogen in the methanamine group is the only atom in the compound that can potentially be a hydrogen bond acceptor3. To form a salt (terbinafine HCl, discussed later), the H+ from HCl would attach here1. A hydrogen bond, if formed, is relatively stronger than other types of intermolecular forces such as dipole-dipole forces and London dispersion forces1. Dipole-dipole forces exists when there is a slight electronegativity difference between molecules; they are less evident in terbinafine as much of the molecule consists of carbons and hydrogens only and there is very little difference in electronegativity between them1. London dispersion forces exist in all molecules1.
G: Consequences of Intermolecular Forces (1)
Should the nitrogen hydrogen bond with another molecule, there would be an increase in polarity, making the drug more hydrophilic and less lipophilic1,3. This translates to a higher solubility in water and a lower solubility in lipid1. Reduced lipid solubility implies lower absorption rates as it may be more difficult for terbinafine to pass through membranes1. However, since a drug must first be dissolved before it is absorbed, it is more important for terbinafine to dissolve in water than in lipid4. This hydrogen bond, a type of dipole-dipole bonding, is important for water solubility1. An application of this consequence is evident in the formation of terbinafine's salt form, terbinafine HCl. The acidic H+ from HCl would attach at the site of the tertiary amine, a basic site1. Once this occurs, it may facilitate drug-protein interactions, as proteins are commonly negatively charged, and will interact with the positively charged salt. In terms of drug-drug interactions, the basic tertiary amine may react with acidic drugs, or inhibit the binding of some basic drugs based on the protein receptor binding.
H: Biological Absorption (1)
Terbinafine is usually administered orally as a salt - terbinafine HCl. Over 70% is absorbed in the gastrointestinal tract, due to its lipophilicity7. After first-pass metabolism, the bioavailability of terbinafine HCl is about 40%5. A recent report shows that absorption is not affected by the presence of food7,10. However, a previous, alternate source states that when terbinafine is taken with food, the bioavailability can be increased to 60%; nonetheless this is not clinically important8. Maximum plasma concentrations are usually reached within 2 hours of oral administration10.
Terbinafine is also available as a cream and a spray, and these forms are absorbed topically through the skin into the affected area.
I: Physicochemical Reason for Observed Absorption
Terbinafine is lipophilic, so it can be well absorbed through the cell membranes in the body. The small intestine, which has a great amount of surface area, is the main site of absorption for oral terbinafine4. Its basicity also accounts for the speed of absorption4. Prior to entering the small intestine, since terbinafine is basic, it will be readily dissolved in the acidic environment of the stomach, allowing it to be dissolved later4. In the small intestine, where the pH is strongly basic, terbinafine will revert to its basic, unionized form, which is favored in absorption1. There are few obstacles that prevent terbinafine from passing through the membranes of the small intestine, so over 70% of orally administered terbinafine is well absorbed5.
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The primary mechanism for distribution of terbinafine is protein binding, as over 99% of terbinafine binds to protein7. This allows for an even distribution in plasma7. The plasma concentration-time profile of terbinafine is triphasic6. In plasma, the half-life of distribution is 1.1 hours6. (The other 2 phases are elimination phases, see part M.) Terbinafine, in addition to its lipophilicity, is also keratophilic (skin-loving); hence it distributes readily throughout adipose tissue, the dermis, epidermis, and nails5. Terbinafine diffuses rapidly from the blood vessels, through the dermis and epidermis, and makes its way to the stratum corneum through the sebum6,7. A small amount is incorporated into the basal keratinocytes and diffuses through the dermis and epidermis6. Terbinafine is not detected in the eccrine sweat glands so it likely does not pass through there6. The concentrations of terbinafine in the nail plate, hair follicles, sebum-rich skin, and adipose tissue greatly exceed those in the plasma (by a factor of 75 after 12 days)6,7. When long-term therapy is discontinued, terbinafine still remains in the skin and nails for a long time (up to 36 weeks)6.
K: Physicochemical Reason for Observed Distribution
The distribution of the drug is mainly due to its lipophilicity and its affinity for protein7. Since the molecule consists almost entirely of carbon-hydrogen bonds and the two elements have very similar electronegativity, it is highly non-polar and therefore lipophilic. This favors diffusion through many membranes in the body into the drug's targets. Its lipophilicity also allows it to be distributed via the sebum to its sites of action7. However, prior to absorption, a drug must first be solvated4. Since terbinafine is only slightly soluble in water (see part C), it is often administered in its salt form, terbinafine HCl, to enhance dissolution in the aqueous, acidic environment of the stomach1,2. Terbinafine's affinity for protein allows it to be 99% bound, so it can distribute itself through the blood to its site of action7. Also, terbinafine's keratophilicity favors distribution to the keratinous stratum corneum, allowing it to reach its targeted site of action6.
As stated earlier, terbinafine undergoes first-pass metabolism in the liver5. The primary mechanisms of metabolism are N-demethylation of the nitrogen atom from the tertiary amine group and oxidation of the tertiary butyl group6,7. Both of these reactions are phase 1 metabolic reactions1. Another mechanism is the arene oxide formation and hydrolysis to form a dihydrodiol7. Less than 5% of hepatic CYP450 enzymes are involved in the metabolism of terbinafine7. Fifteen metabolites are known, but none of them are active as antifungal agents6,7.
Metabolites, amounting to approximately 70-80% of an administered dose, is excreted in the urine, while the rest is excreted in the feces5,7. It is speculated that passive tubular reabsorption in the distal tubule probably contributes most to urine formation (see part N below)9. The plasma elimination half-lives are 16 and 100 hours after an oral dose of 250 mg6. Once the drug has reached the dermis, epidermis, hair, and nails, the average elimination half-life is 24 to 28 days6.
N: Physicochemical Reason for Observed Elimination (1)
Terbinafine, like many other drugs, is primarily excreted through the urine7. Since terbinafine binds strongly to protein, it is unlikely to undergo passive filtration in the glomerulus because this process is limited to free drugs9. It is also unlikely for terbinafine to undergo active tubular secretion as transport proteins in this system transport ions only9. Consequently, the main way of elimination is probably passive tubular reabsorption9. Terbinafine is unionized and lipid soluble, matching the requirement for passive tubular reabsorption9. To be excreted via urine, the non-polar terbinafine is made more polar via phase I and phase II metabolic reactions; this is done primarily by converting the terminal methyl group into an alcohol and then a carboxylic acid group, or by converting the tertiary amine group to a secondary amine group11. These transformations cause a sufficient change in polarity to allow the metabolites of terbinafine to be excreted in urine11. The unabsorbed drugs in the small intestine will eventually be eliminated as feces.
O: Molecular Mechanism of Drug Action (1)
Give in one sentence the mechanism of drug action and describe if there is any involvement of physicochemical properties of the drug?
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Terbinafine HCl distributes itself rapidly to its target organs due to its lipophilicity and interferes with fungal sterol biosynthesis by inhibiting squalene epoxidase in making ergosterol, which is need for fungal cell walls; the decrease in ergosterol prevents reproduction of fungi.
There is no direct involvement of the physicochemical properties of the drug on mechanism; however the drug's lipophilicity, keratophilicity and other physicochemical properties help it reach the skin, the main site of action5.
P: Qualitative Analysis (1)
Terbinafine HCl can be assayed qualitatively by high-performance thin layer chromatography13. Tablet samples are prepared by powdering and dissolving in methanol to produce a 1µL solution to be applied for a TLC plate for analysis13. Likewise, cream samples are prepared by warming with methanol in a water bath with shaking. Chromatography is performed with toluene-ethyl acetate-formic acid (4:5:5:5:0.1 volume-to-volume ratio) as a mobile phase13. A relatively pure sample of terbinafine HCl was well resolved at RF = 0.31 ± 0.02, and can be used as a standard of comparison with other samples are analyzed13. This method is also used to indicate drug stability13 (see D: Chemical Stability).
Q: Quantitative Analysis (1)
Terbinafine HCl can be assayed quantitatively by an ion-pair reversed phase chromatographic method, with UV detection14. A mobile phase containing sodium 1-heptanesulfonate was used as the ion-pair forming agent14. Major factors that might influence the assay were studied, and the optimal conditions for analysis included a low pH at 2.0, a 0.2% ion-pair forming agent concentration for an optimal retention time, and a temperature of 250C14. The pH was adjusted with orto-phosphoric acid and acetonitrile in a 60/40 volume-to-volume ratio14. After UV detection of various concentrations at 220 nm, producing several chromatographic peaks, it is found that there is a linear correlation between the two (concentrations and peaks)14. Thus, any terbinafine sample, prepared in such a mobile phase under the specified conditions for chromatographic analysis, can be analyzed in this way for determination of concentration14.
When terbinafine HCl is analyzed in a Dynamic Scanning Calorimeter (DSC), a sharp peak is observed at 206.80C15. This is the melting point of terbinafine HCl, and is therefore endothermic; that is, endothermic is downwards in the DSC15. Since the following DSC graph is for terbinafine HCl (as opposed to terbinafine, the parent drug), a major difference would be in its melting point, as melting points between a parent drug and its salt will be different. Specifically, the melting range of terbinafine is 1950C to 1980C, approximately 100C lower than its HCl salt2. (Drugbank) (Asian Journal of Pharmaceutics)
S: Salt of your Drug (1)
Terbinafine is often made in to a salt - terbinafine HCl - for oral administration. This is made by dissociating terbinafine in HCl, as they will dissociate into their respective ions1. The positively charged, acidic H+ from HCl will be attracted to the lone pair on the basic nitrogen of the methanamine, forming an intermolecular ionic bond1. Removing the solvent will allow the crystallization of the salt, which can be further purified and manufactured for oral administration1. Physicochemically, terbinafine HCl has a melting point approximately 100C higher, and is more soluble in water, than terbinafine2,15. The presence of an ionic bond and the increased molecular weight will likely result in a higher boiling point in the salt form1. The overall drug action of terbinafine is not impacted by salt formation1.
T: Drug Application (1)
Terbinafine is frequently administered as a salt, improving its water solubility in the stomach to allow for absorption in the small intestines; its lipophilicity allows it to be easily absorbed through the GI tract and other membranes to reach its site of action. Thus oral administration would be effective for terbinafine.