PRODUCTS

THEOPHYLLINE

Theophylline is a methylxanthine that acts as a weak bronchodilator.
Theophylline is useful for chronic therapy and is not helpful in acute exacerbations.
Theophylline is a methylxanthine alkaloid that is a competitive inhibitor of phosphodiesterase, Theophylline is also a non-selective antagonist of adenosine A receptors (Ki = 14 μM for A1 and A2).

CAS Number: 58-55-9
Molecular Formula: C7H8N4O2
Molecular Weight: 180.16
EINECS Number: 200-385-7

Synonyms: 1,3-dimethyl-xanthin;1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-;3,7-dihydro-1,3-dimethyl-1h-purine-6-dione;3h)-dione,1,3-dimethyl-purine-6(1h;6-dione,3,7-dihydro-1,3-dimethyl-1H-Purine-2;accurbron;Acet-theocin;aerolate

Theophylline is a dimethylxanthine having the two methyl groups located at positions 1 and 3.
Theophylline is structurally similar to caffeine and is found in green and black tea.
Theophylline has a role as a vasodilator agent, a bronchodilator agent, a muscle relaxant, an EC 3.1.4, (phosphoric diester hydrolase) inhibitor, an anti-asthmatic drug, an anti-inflammatory agent, an immunomodulator, an adenosine receptor antagonist, a drug metabolite, a fungal metabolite and a human blood serum metabolite.

Theophylline induces relaxation of feline bronchiole smooth muscle precontracted with acetylcholine (EC40 = 117 μM; EC80 = 208 μM).
Formulations containing theophylline have been used in the treatment of asthma and chronic obstructive pulmonary disease (COPD).
Theophylline is a naturally occurring methylxanthine alkaloid and a well-established pharmaceutical compound belonging to the xanthine family.

Theophylline is chemically related to caffeine and theobromine and occurs naturally in small amounts in tea leaves and other plant materials.
The chemical name of theophylline is 1,3-dimethyl-7H-purine-2,6-dione.
Its molecular formula is C₇H₈N₄O₂, and its molecular weight is approximately 180.16 g/mol.

Theophylline is identified by CAS No. 58-55-9.
It is also known as 1,3-dimethylxanthine, and the name theophyllin is another commonly encountered synonym.
In its pure form, theophylline is generally described as an odorless white crystalline powder with a bitter taste.

Theophyllines crystalline nature is associated with the planar heterocyclic xanthine structure containing several nitrogen atoms and two carbonyl groups.
The molecule contains a fused purine-2,6-dione ring system.
Two methyl groups are attached to the nitrogen atoms at positions 1 and 3, distinguishing theophylline structurally from related methylxanthines such as caffeine and theobromine.

The presence of several nitrogen and oxygen atoms gives theophylline significant hydrogen-bonding capability.
PubChem reports one hydrogen-bond donor and three hydrogen-bond acceptors, while its calculated topological polar surface area is approximately 69.3 Å².
Theophylline has relatively low lipophilicity compared with many conventional pharmaceutical compounds.

Its calculated XLogP3 value is approximately zero, reflecting the influence of its polar heterocyclic structure.
Pharmacologically, theophylline is classified primarily as a bronchodilator and methylxanthine derivative.
Theophylline has historically been used to help relieve reversible airflow obstruction associated with conditions such as asthma and other chronic respiratory diseases.

One of its principal biological actions is relaxation of bronchial smooth muscle.
This produces bronchodilation, which can increase airway diameter and facilitate airflow through the respiratory tract.
Theophylline also acts as a phosphodiesterase inhibitor.

Inhibition of phosphodiesterase enzymes can increase intracellular cyclic AMP levels, contributing to relaxation of smooth muscle and other pharmacological effects.
Another important mechanism involves adenosine receptors.
Theophylline can antagonize adenosine-mediated effects, contributing to its effects on airway smooth muscle and helping explain some of its stimulant and cardiovascular actions.

Theophylline has also been investigated for anti-inflammatory effects in respiratory diseases.
Its pharmacological activity is therefore broader than simple bronchodilation, although the clinical importance of individual mechanisms depends on dose and therapeutic context.
Theophylline has a relatively narrow therapeutic index.

This means that the difference between concentrations providing therapeutic effects and concentrations associated with toxicity can be relatively small, making appropriate dosing and monitoring particularly important when it is used as a medicine.
At excessive concentrations, theophylline can produce significant systemic effects.
Reported manifestations of toxicity include nausea, vomiting, gastrointestinal disturbances, tremor, insomnia, tachycardia, cardiac arrhythmias, and, in severe cases, seizures.

Theophylline is also a pharmacologically active natural product rather than simply an industrial chemical intermediate.
Its biological activity has resulted in applications across pharmaceutical research, analytical chemistry, drug development, and clinical medicine.
Theophylline can exist in different solid-state forms, including anhydrous and hydrated forms.

Theophylline is structurally related to caffeine, but the two compounds are not identical.
Theophylline contains two methyl groups, whereas caffeine contains three, resulting in differences in molecular structure, pharmacological activity, metabolism, and potency.

It is also related to theobromine, another naturally occurring methylxanthine found particularly in cocoa.
The three compounds share the xanthine core but differ in the positions and number of methyl substituents, which contributes to their different biological properties.
Theophylline is a crystalline methylxanthine compound with the molecular formula C₇H₈N₄O₂ and CAS No. 58-55-9.

Its combination of a nitrogen-rich heterocyclic structure, pharmacological activity, bronchodilating properties, and relationship to naturally occurring methylxanthines makes it an important compound in pharmaceutical and chemical research.
Theophylline is particularly interesting from a solid-state chemistry perspective because it exhibits polymorphism, meaning that the same chemical compound can crystallize in different structural arrangements.
Several anhydrous forms of theophylline have been identified, and these forms can differ in stability, solubility, and dissolution behavior.

Theophylline also forms a monohydrate, in which water molecules are incorporated into the crystal structure.
The balance between anhydrous and hydrated forms depends strongly on the surrounding moisture conditions and water activity.
The different crystal forms are important during pharmaceutical processing because changes in humidity or temperature can cause one solid form to transform into another.

Such transformations can modify the dissolution characteristics of the final material even though its molecular composition remains unchanged.
Theophylline monohydrate can undergo dehydration when exposed to suitable thermal conditions.
The dehydration process has been investigated using techniques such as differential scanning calorimetry, thermogravimetric analysis, and crystallographic methods.

The anhydrous polymorphs of theophylline have also been studied extensively to understand their thermodynamic stability.
One reported anhydrous form, designated Form IV, was found to be the most thermodynamically stable anhydrous polymorph under the conditions investigated.
The solid-state behavior of theophylline makes it a useful model compound for studying pharmaceutical crystallization and polymorphism.

Theophylline have used it to investigate how crystal structure, hydration, temperature, relative humidity, and solvent composition influence the properties of an active pharmaceutical ingredient.
Theophylline can be characterized using several analytical techniques, including infrared spectroscopy, ultraviolet spectroscopy, mass spectrometry, chromatography, and thermal analysis.
These methods can be used to identify the compound, determine its purity, distinguish related methylxanthines, and investigate changes in its solid-state structure.

High-performance liquid chromatography has been widely used for the determination of theophylline in pharmaceutical formulations and biological samples.
Chromatographic methods can also separate theophylline from metabolites and other methylxanthines, making the compound suitable for quantitative analytical studies.

Melting point: 271-273 °C
Boiling point: 312.97°C (rough estimate)
Density: 1.3640 (rough estimate)
refractive index: 1.6700 (estimate)
Flash point: 11 °C
storage temp.: 2-8°C
solubility: 0.1 M HCl: soluble
form: powder
pka: 8.77(at 25℃)
color: white
Water Solubility: 8.3 g/L (20 ºC)
Merck: 14,9285
BRN: 13463
Henry's Law Constant: 5.5×108 mol/(m3Pa) at 25℃, HSDB (2015)
BCS Class: 3,1
Stability: Stable. Incompatible with strong oxidizing agents.
Cosmetics Ingredients Functions: SKIN CONDITIONING - MISCELLANEOUS
InChI: 1S/C7H8N4O2/c1-10-5-4(8-3-9-5)6(12)11(2)7(10)13/h3H,1-2H3,(H,8,9)
InChIKey: ZFXYFBGIUFBOJW-UHFFFAOYSA-N
SMILES: CN1C(=O)N(C)c2[nH]cnc2C1=O
LogP: -0.020
FDA 21 CFR: 310.545
CAS DataBase Reference: 58-55-9(CAS DataBase Reference)
EWG's Food Scores: 1-4
NCI Dictionary of Cancer Terms: theophylline
FDA UNII: 0I55128JYK
NCI Drug Dictionary: Constant-T
ATC code: R03DA04
IARC: 3 (Vol. 51) 1991

Theophylline was firstly extracted from tea leaves and chemically identified by the German biologist Albrecht Kossel.
A cup of tea contains about 1mg/mL theophylline.
In 1895, a chemical synthesis of theophylline starting with 1,3-dimethyluric acid was described by Emil Fischer and Lorenz Ach.

Theophylline was synthesized by Wilhelm Traube in 1900.
Aminophylline, a derivative of theophylline ethylenediamine, is widely used due to its greater aqueous solubility.
Theophylline should be used with caution in patientswith myocardial disease, liver disease, and acutemyocardial infarction.

The half-life of theophylline isprolonged in patients with congestive heart failure.Because of its narrow margin of safety, extreme cautionis warranted when coadministering drugs, such as cimetidineor zileuton, that may interfere with the metabolismof theophylline.
Indeed, coadministration of zileutonwith theophylline is contraindicated.
Theophylline is alsoprudent to be careful when using theophylline in patientswith a history of seizures.

Theophylline has relatively limited solubility in water at room temperature, although its solubility increases substantially when the temperature rises.
Theophylline is also more soluble in alkaline solutions, which is related to the weakly acidic character of the molecule.
Theophylline has a reported pKa of approximately 8.77 at 25 °C, reflecting the ionization behavior of its heterocyclic structure.

This property can influence its solubility, formulation behavior, and interaction with different chemical environments.
Theophylline has a high melting point of approximately 270–274 °C, consistent with its crystalline structure and strong intermolecular interactions.
This thermal characteristic is useful when distinguishing theophylline from related methylxanthines during analytical and pharmaceutical characterization.

Theophylline can exist in anhydrous and monohydrate forms, with the latter containing water incorporated into its crystal structure.
Differences between these forms can affect physical properties such as crystallinity, water content, dissolution behavior, and processing characteristics.
From a chemical perspective, theophylline contains a fused nitrogen-containing heterocyclic system with two carbonyl groups.

The combination of ring nitrogens and carbonyl functionalities gives the molecule its characteristic hydrogen-bonding and polarity profile.
Theophylline is also important as a model methylxanthine compound in pharmacokinetic and biochemical studies.
Its absorption, distribution, metabolism, and elimination have been extensively investigated because relatively small changes in its metabolic clearance can substantially influence its concentration in biological systems.

After oral administration, theophylline is rapidly absorbed, particularly when supplied as a solution or immediate-release solid dosage form.
In adults and children older than one year, approximately 90% of the absorbed dose is metabolized in the liver rather than being eliminated unchanged.
The major metabolic pathways include demethylation and hydroxylation, producing compounds such as 1-methylxanthine, 3-methylxanthine, and 1,3-dimethyluric acid.

These metabolites are useful in pharmacological and analytical studies because they provide information about how theophylline is processed within the body.
The elimination behavior of theophylline can vary considerably between individuals.
Factors including age, liver function, smoking, concurrent illnesses, diet, and other medicines can alter clearance and therefore change the time the compound remains in the body.

Because of this variability, theophylline has historically been an important example of a compound for which pharmacokinetic monitoring is particularly relevant.
Theophylline variable metabolism and relatively narrow margin between effective and toxic concentrations have also made it a useful compound for studying drug metabolism and therapeutic drug monitoring.
Theophylline has relatively low volatility under ordinary environmental conditions.

Theophylline estimated vapor pressure is very low, and it is therefore not expected to readily volatilize from water, moist soil, or dry soil surfaces.
Its physicochemical behavior is also influenced by pH because the molecule possesses weak acidic and basic characteristics.
Theophylline solutions are generally stable across a broad pH range, although strongly alkaline conditions can eventually promote decomposition and apparent ring-opening reactions.

The combination of polymorphism, hydration, solubility, and pH-dependent behavior makes theophylline an extensively studied compound in pharmaceutical chemistry.
These characteristics are important not only for its medicinal applications but also for formulation development, crystallization control, analytical chemistry, and solid-state research.

Uses:
Theophylline derivative with diuretic, cardiac stimulant and smooth muscle relaxant activities; isomeric with theobromine. Small amounts occur in tea. Bronchodilator.
Theophylline is tonic and skin conditioning.
Its cosmetic activity is not clearly or definitively established.

Theophylline is most often found in anti-cellulite products.
Theophylline is in the same family of bio chemicals as caffeine.
Theophylline is naturally occurring in tea.

The principal use of theophylline is in the management of asthma.
Theophylline is also used to treat the reversible component of airway obstruction associated with chronic obstructive pulmonary disease and to relieve dyspnea associated with pulmonary edema that develops from congestive heart failure.
Theophylline is primarily used as a bronchodilator in the treatment of chronic respiratory conditions associated with reversible airway obstruction.

Theophylline has been used particularly in the management of asthma and other chronic lung diseases such as emphysema and chronic bronchitis.
In asthma treatment, theophylline helps relax bronchial smooth muscle and can reduce airway obstruction.
Its pharmacological effects can also decrease the responsiveness of the airways to certain stimuli, providing an additional protective effect beyond direct bronchodilation.

Theophylline has also been used in patients with chronic obstructive pulmonary disease (COPD).
Clinical studies have reported reductions in dyspnea and air trapping, together with improvements in the work of breathing and diaphragmatic muscle contractility.
Extended-release theophylline formulations are designed for long-term management rather than rapid treatment of acute bronchospasm.

The controlled-release form can provide prolonged exposure and has been developed in dosage forms intended for once-daily or other extended dosing schedules.
Theophylline has historically been incorporated into oral pharmaceutical formulations, including conventional tablets, extended-release tablets, capsules, and oral solutions.
Different formulations allow manufacturers to modify the rate at which theophylline becomes available after administration.

Theophylline is also used in pharmaceutical research as a well-characterized methylxanthine model compound.
Theophylline established pharmacological activity and extensively studied metabolism make it useful for investigating bronchodilator mechanisms, methylxanthine pharmacology, and drug disposition.
Another important application is in therapeutic drug monitoring research.

Because theophylline clearance can vary substantially between individuals and changes in serum concentration can have important clinical consequences, the compound has been widely studied in pharmacokinetic investigations and analytical monitoring.
Theophylline is frequently used as an analytical reference compound in the development and validation of chromatographic methods.
High-performance liquid chromatography and related techniques can be used to quantify theophylline in pharmaceutical products and biological matrices, as well as to distinguish it from structurally related methylxanthines.

Theophylline is also useful in drug metabolism studies because its principal metabolites are well characterized.
Theophylline can monitor theophylline and its metabolites to investigate hepatic metabolic pathways, enzyme activity, clearance mechanisms, and pharmacokinetic differences between experimental conditions.
Theophylline has additionally served as a model substance in pharmaceutical formulation research.

Its polymorphism, hydration behavior, relatively low aqueous solubility, and sensitivity to crystallization conditions make it particularly useful for studying solid-state properties of active pharmaceutical ingredients.
Theophylline is used in studies involving crystal engineering and pharmaceutical crystallization.
Anhydrous and hydrated forms provide a practical system for examining how crystal structure, moisture, temperature, and processing conditions influence the physical properties of pharmaceutical solids.

Theophylline ability to form different solid-state forms also makes theophylline useful in research on polymorphism and phase transformations.
These studies can help researchers understand how changes in crystal structure influence dissolution, stability, processing behavior, and other characteristics relevant to pharmaceutical manufacturing.
Theophylline is further employed in spectroscopic and thermal analysis research.

Techniques such as infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and X-ray diffraction can be applied to characterize the compound and investigate its crystalline or hydrated forms.
Because its chemical structure is closely related to other methylxanthines, theophylline is also used in comparative studies involving caffeine, theobromine, and related purine derivatives.
Such research can examine differences in molecular structure, biological activity, metabolism, solubility, and physicochemical behavior.

The combination of established pharmaceutical applications and well-defined chemical properties makes theophylline valuable not only as an active pharmaceutical ingredient but also as a research compound, analytical reference material, and model substance for pharmaceutical chemistry.
Theophylline is also used in pharmaceutical development as an active pharmaceutical ingredient (API) in oral formulations intended to provide sustained bronchodilator activity.
Its established pharmacological profile has supported the development of immediate-release and modified-release dosage forms for respiratory disease management.

Theophylline has applications in the development of extended-release tablets and capsules, where formulation technologies are used to control the release of the active ingredient over an extended period.
This approach is particularly relevant because maintaining appropriate theophylline concentrations can be important when the compound is used for long-term respiratory treatment.
Theophylline is also used in pharmaceutical formulation research as a model compound for investigating drug release.

Its well-characterized solubility, crystallinity, hydration behavior, and polymorphism make it useful when evaluating how formulation composition and processing conditions influence dissolution.
Another important use is in quality control of pharmaceutical products.
Theophylline can be identified and quantified in tablets, capsules, solutions, and other pharmaceutical preparations using established analytical procedures.

Theophylline is available as a pharmaceutical reference standard for analytical laboratories.
Reference materials are used to establish the identity, purity, assay, and analytical performance of methods applied to theophylline-containing products.
It is also used as a USP, European Pharmacopoeia, and British Pharmacopoeia reference material in analytical applications.

These standardized materials can support pharmaceutical testing, method validation, impurity investigations, and comparison of analytical results between laboratories.
Theophylline has applications in chromatographic method development, particularly for high-performance liquid chromatography.
Its predictable chemical behavior and availability as a certified reference material make it suitable for developing quantitative methods for pharmaceutical and biological samples.

Theophylline is also used in bioanalytical research to measure drug concentrations in biological matrices.
Analytical determination of theophylline can be used in pharmacokinetic investigations and studies examining absorption, metabolism, distribution, and elimination.
Theophylline and its metabolites are useful in drug metabolism research because several metabolic products have been well characterized.

Theophylline can therefore use the compound to investigate metabolic pathways and changes in drug clearance under different experimental conditions.
Theophylline is further employed as a model compound in pharmaceutical crystallization studies.
Its ability to occur in anhydrous and hydrated forms provides researchers with a practical system for examining crystallization, dehydration, hydration, and solid-state transformations.

Theophylline polymorphic behavior also makes theophylline valuable in crystal engineering research.
Theophylline can investigate how different crystal arrangements influence properties such as stability, dissolution rate, and thermodynamic behavior.
Theophylline is used in thermal analysis studies to examine changes occurring during heating and cooling.

Differential scanning calorimetry and thermogravimetric analysis can be applied to investigate melting, dehydration, phase transitions, and thermal stability.
Theophylline is also useful in spectroscopic analysis and chemical identification.
Infrared absorption methods have been used for identification, while chromatographic and spectroscopic techniques can support quantitative analysis and purity assessment.

Safety Profile:
Human poison by ingestion, parenteral, intravenous, and rectal routes.
Experimental poison by multiple routes.
An experimental teratogen. Human systemic effects: coma, convulsions or effect on seizure threshold, cyanosis, EKG changes, fever and other metabolic effects, heart arrhythmias, heart rate change, hyperglycemia, metabolic acidosis, nausea or vomiting, potassium-level changes, respiratory stimulation, salivary gland changes, somnolence, tremor.

Human mutation data reported.
Used as a dturetic, cardtac stimulant, smooth muscle relaxant, and to treat asthma.
Theophylline has a narrow therapeutic index, meaning that the difference between an effective concentration and a toxic concentration can be relatively small.

For this reason, excessive exposure can produce significant adverse effects and toxicity, particularly when blood concentrations become elevated.
The most common adverse effects associated with theophylline involve the gastrointestinal system.
Nausea, vomiting, abdominal discomfort, increased gastric acid secretion, diarrhea, and loss of appetite can occur, particularly when exposure becomes excessive.

Theophylline can also stimulate the central nervous system.
Headache, irritability, restlessness, nervousness, insomnia, dizziness, and tremor may occur, while severe toxicity can progress to muscle twitching and seizures.
Cardiovascular effects represent another important hazard associated with excessive theophylline exposure.

Palpitations, tachycardia, hypotension, and cardiac arrhythmias have been reported, with serious rhythm disturbances becoming more likely during severe toxicity.
Acute or chronic overdose can produce substantially more serious effects than routine therapeutic exposure.
Severe poisoning may involve persistent vomiting, dehydration, cardiac arrhythmias, hypotension, seizures, and potentially life-threatening cardiorespiratory complications.

Theophylline toxicity can occur following a single excessive dose or after repeated doses that are too high for an individual's rate of drug clearance.
Chronic toxicity may therefore develop even when individual doses do not appear exceptionally large if clearance has been reduced.
Several factors can alter theophylline clearance and increase the potential for toxicity.

Changes in liver function, age, smoking status, illness, and interactions with other medicines can affect circulating theophylline concentrations and therefore influence its safety profile.
Theophylline can interact with a wide range of medicines because its metabolism is influenced by hepatic enzyme activity.
Such interactions can either increase or decrease theophylline concentrations, making careful consideration of concurrent medications important when the compound is used therapeutically.

Supply Of Theophylline:
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