Chemical Structures and Excipient Profile of Drugs

DRUG AND EXCIPIENT PROFILE

CAFFEINE

Chemical structure:
Mol. Weight: Average: 194.1906
Melting point: 238 °C
State: solid
Water solubility: 2.16E+004 mg/L (at 25 °C)
Half Life: 3 – 7 hours in geriatrics , 65 – 130 hours in pediatrics
Protein Binding: Low protein binding (25 – 36%)
Absorption: absorbed after oral and parenteral administration. The peak plasma level of caffeine ranges from 6 to 10mg/L and the mean time to reach peak concentration ranged from 30 minutes to 2 hours.
Pharmacology: Caffeine is a naturally occurring xanthine derivative like theobromine and the bronchodilator theophylline. It is used as a CNS stimulant, mild diuretic, and respiratory stimulant (in neonates). Often combined with analgesics or with ergot alkaloids, caffeine is used to treat migraine and other types of headache. Over the counter, caffeine is used to treat drowsiness or mild water-weight gain.
Mechanism of Action: Caffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. This action was previously believed to be due primarily to increased intracellular cyclic 3′,5′-adenosine monophosphate (cyclic AMP) following inhibition of phosphodiesterase, the enzyme that degrades cyclic AMP. Xanthines such as caffeine act as antagonists at adenosine-receptors within the plasma membrane of virtually every cell. As adenosine acts as an autocoid, inhibiting the release of neurotransmitters from presynaptic sites but augmenting the actions of nor epinephrine or angiotensin, antagonist of adenosine receptors promotes neurotransmitter release. This explains the stimulatory effects of caffeine. Blockage of the adenosine A1 receptor in the heart leads to the accelerated, pronounced “pounding” of the heart upon caffeine intake.
Indication: For management of fatigue, orthostatic hypotension, and for the short term treatment of apnea of prematurity in neonates.
Toxicity: LD₅₀= 127 mg/kg (oral dose in mice)

ERGOTAMINE

Chemical structure:
Mol. Weight: Average: 581.6615
Melting point: 213.5 °C
State: solid state
Water solubility: Slightly soluble
Half Life: 2 hours
Absorption: The bioavailability of sublingual ergotamine has not been determined.
Pharmacology: Ergotamine is a vasoconstrictor and alpha adrenoreceptor antagonist. The pharmacology of ergotamine is extremely complex; some of its actions are unrelated to each other, and even mutually antagonistic. The drug has partial agonist and antagonist activity against tryptaminergic, dopaminergic and alpha adrenergic receptors depending upon the site, and is highly active uterine stimulant. It causes constriction of peripheral and cranial blood vessels and producing depression of central vasomotor centers. The pain of a migraine attack is due to increased amplitude of pulsations in the cranial arteries, especially the meningeal branches of the external carotid artery. Ergotamine reduces extra cranial blood flow, causes a decline in the amplitude of pulsation in the cranial arteries, and decreases hyper perfusion of the territory of the basilar artery. It does not reduce cerebral hemispheric blood flow.
Mechanism of Action: Ergotamine acts on migraine by one of the two proposed mechanisms:

1) activation of 5-HT_1D receptors located on intracranial blood vessels, including those on arteriole-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine, and

2) Activation of 5-HT_1D receptors on sensory nerve endings of the trigeminal system which results in inhibition of pro-inflammatory neuropeptide release.

Indication: For use as therapy to abort or prevent vascular type of headache, e.g., migraine, migraine variants, or so called “histaminic cephalalgia”.
Toxicity: Signs of overexposure including irritation, nausea, vomiting, headache, diarrhea, thirst, coldness of skin, pruritus, weak pulse, numbness, tingling of extremities, and confusion.

CYCLIZINE

Chemical structure:
Mol. Weight: Average: 266.38
Melting point: 105.5 °C
State: solid state
Water solubility: 1000 mg/L (at 25 °C)
Half Life: 20 hours

Pharmacology: Cyclizine is a piperazine derivative antihistamine used as antivertigo/antiemetic agent. Cyclizine is used in the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness. Additionally, it has been used in the management of vertigo in disease affecting the vestibular apparatus. The mechanism by which cyclizine exerts its antiemetic and antivertigo effects is not been fully elucidated, its central anticholinergic properties are partially responsible. The drug depresses labyrinth excitability and vestibular stimulation, and it may affects medullary chemoreceptor trigger zone. It also possesses anticholinergic, antihistaminic, central nervous system depressant, and local anesthetic effects.
Mechanism of Action: Vomiting (emesis) is essentially a protective mechanism for removing irritant and harmful substances from the upper GI tract. Emesis is controlled by the vomiting centre in the medulla region of the brain, an important part of which is the chemotrigger zone (CTZ). The vomiting centre possesse neurons which are rich in muscarinic cholinergic and histamine containing synapses. These types of neurons are especially involved in transmission from the vestibular apparatus to the vomiting centre. Motion sickness involves overstimulation of the pathways due to various sensory stimuli. Hence the action of cyclizine which acts to block the histamine receptors in the vomiting centre and thus reducing the activity along these pathways. Furthermore since cyclizine possesses anti-cholinergic properties as well, the muscarinic receptors are similarly blocked.
Indication: For prevention and treatment of the nausea, vomiting, and dizziness that are associated with motion sickness, and vertigo (dizziness caused by other medical problems).

EXCIPIENT PROFILE

MANNITOL

Synonym: D –mannite, manna sugar, cordycepic acid, pearlitol.
Emperical Formula: C₆H₁₄O₆
Molecular Weight: Approx. 182.17
Description: Mannitol is a white , Odorless, crystalline powder or free flowing granules .It has sweet taste , approximately as sweet as glucose and half as sweet as sucrose, impart the cooling sensation in the mouth.
Density, bulk: 0.430 g/cm³ for powder 0.7g/cm³for granules
Density, tapped: 0.734gm /cm³for powder, 0.8gm/cm³ for granules.
Solubility: Freely soluble in water, very slightly soluble in ethanol (96 per cent). It shows polymorphism.
Incompatibility: Mannitol is incompatible with xytilol infusion and may form complexes with some metals such as aluminum, copper and iron. Mannitol was found to reduce bioavailability of cemitidine compared to sucrose.
Handling precaution: Mannitol may be irritate to eye, eye protection is recommended.
Uses: Diluents (10-90%w/w), mannitol is used as excipient in the manufacture of chewable tablet because of it^s negative heat of solution, sweetness and mouth feel.

MICROCRYSTALLINE CELLULOSE

Synonym: Cellulose gel, crystalline cellulose, Avicel PH 101, 102
Empirical Formula: (C₆H₁₀O₅)_n
Molecular weight: Approx.36000
Description: Purified, partially depolymerised cellulose occurs as a white, tasteless odorless, crystalline, powder that is composed of porous particles available in different particle size grades with different properties , i.e. 101 ,102
Bulk Density: 0.28gm/cm ³
Tapped Density: 0.43gm/cm³
Solubility: Insoluble in water, dilute acids and most organic solvents .Slightly soluble in sodium hydroxide solution.
Stability and storage condition: Stable and hygroscopic. Store in a well – closed container.
Incompatibility: None cited in the literature.
Handling precautions: No restrictions.
Uses: Tablet binder / diluents (5-20%), tablet disintegrant (5-15%), tablet glidant (5-15%) antiadherent (5-20%), capsule diluents (10-30%)

CROSSCARMELLOSE SODIUM

In a cross linked polymer of carboxymethylcellulose sodium.
Synonym: Ac-DI-Sol;
Molecular formula: C8H16O8
Molecular weight: 240.20784
Description: It occurs as an odorless, white or grayish white powder.
Density, bulk: 0.529gm/cm³
Density, tapped: 0.819gm/cm³
Stability and storage condition: It is stable though hygroscopic material, preserve in well closed container in cool and dry place.
Incompatibilities: The efficacy of disintegration may be slightly reduced in tablet formulation prepared by either the wet granulation or direct compression that contains hygroscopic excipients such as Sorbitol.
Handling precautions: It may be irritant to eye. Eye protection is recommended.
Uses: It is used in oral pharmaceutical formulation as, a disintegrant for capsule, tablets, and granules.

SODIUM STARCH GLYCOLATE

Sodium salt of cross linked partly o- carboxymethylated potato starch..
Synonym: Carboxy methyl cellulose, sodium salt, exeplosol, explotab.
Description: White or almost white free flowing powder, very hygroscopic.
Density, bulk: 0.75gm/cm³
Density, tapped: 0.95gm/cm³
Solubility: Practically insoluble in Methylene chloride. It gives a translucent suspension in water.
Stability and Storage: It is stable and should be stored in a well closed container in cool and dry place.
Incompatibilities: It is incompatible with ascorbic acid.
Handling precautions: Eye protection, glove and a dust mask are recommended.
Uses: It is use in oral pharmaceutical formulation as a disintegrant for capsule, tablet, and granules.

TALC

It is hydrous magnesium silicate may contain a small amount of aluminium silicateand iron.
Nonpropritery Name: Purified Talc (BP), Talc (JP), Talc (USP).
Synonym: A talc, hydrous magnesium calcium silicate; powdered talc.
Empirical Formula: Mg₆ (Si₂O₅) (OH) ₄
Description: A very fine, white to grayish-white, impalpable, odorless, crystalline powder. Adheres readily to skin soft to touch and free from grittiness.
Density, bulk: 19gm/cm³
Density, tapped: 48gm/cm³
Solubility: Insoluble in water, organic solvents, cold acid.
Stability and Storage: Stable, preserve in well closed container.
Incompatibilities: It is incompatible with quaternary ammonium compounds.
Handling Precaution: Eye protection, gloves, and respirator are recommended.
Uses: It is use a s glidant, lubricant (1-10%), Diluents5-30%, Dusting powder 90-99%

MAGNESIUM STEARATE

Synonym: Metallic stearate; octadecanoic acid; magnesium salt; Stearic acid.
Nonproprietary Name: Magnesium Stearate (BP); Magnesium Stearate (JP); Magnesium Stearate (USP).
Empirical Formula: C₃₆H₇₀MgO₄
Molecular Weight: 591.3
Description: Fine, white, precipitated or milled, impalpable powder of low bulk density. Odour and taste are slight but characteristic. The powder is readily adheres to the skin.
Density, bulk: 0.519 gm/cm³
Density, tapped: 0.286gm/cm³
Melting point: 117-150⁰C
Stability And Storage Condition: Stable, non self polymerisable, store in cool and dry place in a well closed container.
Incompatibilities: Incompatable with strong acid substances, alkaline substances, iron salts, avoid mixing with strong oxidizing materials. Use with caution with drugs , which are incompatible with alkali.
Uses: tablet and capsule lubricant, glidant or antiadherent (0.25-2.0%).(Brunye et al., 2010) (Mohammadi and Kanfer, 2005) (Shapiro and Cowan, 2006) (Tsutsumi et al., 2002)