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Diphenhydramine | CAS No: 58-73-1 | GMP-certified suppliers
A medication that provides symptomatic relief of common allergic conditions, itching, and rashes while also supporting short‑term management of insomnia, motion sickness, and nausea.
Therapeutic categories
Primary indications
- Diphenhydramine is a first-generation histamine H1 receptor antagonist (H1 antihistamine) that is widely available as a non-prescription, over-the-counter (OTC) medication
- As an OTC medication, diphenhydramine is typically formulated as tablets and creams indicated for use in treating sneezing, runny nose, itchy/watery eyes, itching of nose or throat, insomnia, pruritis, urticaria, insect bites/stings, allergic rashes, and nausea
- Additionally, when the use of oral diphenhydramine is impractical, there are also prescription-only formulations such as diphenhydramine injection products that are effective in adults and pediatric patients (other than premature infants and neonates) for:
- I) the amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after acute allergic reaction symptoms have been controlled, and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated
Product Snapshot
- Diphenhydramine is a small-molecule antihistamine supplied in extensive oral, topical, and parenteral formulations, including OTC solids/liquids and prescription injectable solutions
- It is used for allergic symptom management, pruritic conditions, motion sickness, and select situations where parenteral antihistaminic or anticholinergic activity is required
- The API supports products authorized in the US and Canada, with both established OTC approvals and certain investigational listings
Clinical Overview
Its pharmacologic activity is driven by inverse agonism at H1 receptors located in respiratory smooth muscle, vascular endothelium, gastrointestinal tissue, cardiac tissue, immune cells, the uterus, and the central nervous system. Blockade of these receptors reduces vascular permeability, vasodilation, and sensory nerve stimulation, thereby moderating histamine‑mediated allergic responses. Central H1 antagonism contributes to its sedative, hypnotic, and antitussive properties.
Diphenhydramine also exerts antimuscarinic effects through competitive antagonism of muscarinic acetylcholine receptors, a feature that supports its use in parkinsonism and contributes to anti‑vertigo and antiemetic actions. Additional activity as a sodium channel blocker has been associated with local anesthetic effects.
Absorption is rapid after oral administration, and its ability to cross the blood–brain barrier leads to pronounced central nervous system effects. Diphenhydramine undergoes hepatic metabolism, including CYP2D6‑mediated pathways, with metabolites excreted primarily in urine. Sedation, cognitive impairment, anticholinergic effects, paradoxical excitation in pediatric patients, and potential QTc prolongation are clinically relevant safety considerations.
For API procurement, suppliers should provide evidence of compliance with pharmacopeial monographs, validated impurity controls consistent with first‑generation antihistamines, and robust management of polymorphism and particle‑size attributes to support consistent formulation performance.
Identification & chemistry
| Generic name | Diphenhydramine |
|---|---|
| Molecule type | Small molecule |
| CAS | 58-73-1 |
| UNII | 8GTS82S83M |
| DrugBank ID | DB01075 |
Pharmacology
| Summary | Diphenhydramine is an inverse agonist of H1 receptors that attenuates histamine‑mediated vascular permeability, smooth muscle activation, and sensory nerve stimulation. It readily enters the CNS, where H1 antagonism produces sedative effects and contributes to antiemetic and antitussive activity. The drug also exhibits antimuscarinic actions and sodium channel blockade, supporting additional effects on vestibular pathways, motor control, and local anesthesia. |
|---|---|
| Mechanism of action | Diphenhydramine predominantly works via the antagonism of H1 (Histamine 1) receptors . Such H1 receptors are located on respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons . When the H1 receptor is stimulated in these tissues it produces a variety of actions including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and the GIT, and eosinophilic chemotaxis that promotes the allergic immune response . Ultimately, diphenhydramine functions as an inverse agonist at H1 receptors, and subsequently reverses effects of histamine on capillaries, reducing allergic reaction symptoms . Moreover, since diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness, and suppressing the medullary cough center . Furthermore, H1 receptors are similar to muscarinic receptors . Consequently, diphenhydramine also acts as an antimuscarinic . It does so by behaving as a competitive antagonist of muscarinic acetylcholine receptors, resulting in its use as an antiparkinson medication . Lastly, diphenhydramine has also demonstrated activity as an intracellular sodium channel blocker, resulting in possible local anesthetic properties . |
| Pharmacodynamics | Diphenhydramine has anti-histaminic (H1-receptor), anti-emetic, anti-vertigo and sedative and hypnotic properties . The anti-histamine action occurs by blocking the spasmogenic and congestive effects of histamine by competing with histamine for H1 receptor sites on effector cells, preventing but not reversing responses mediated by histamine alone . Such receptor sites may be found in the gut, uterus, large blood vessels, bronchial muscles, and elsewhere . Anti-emetic action is by inhibition at the medullary chemoreceptor trigger zone . Anti-vertigo action is by a central antimuscarinic effect on the vestibular apparatus and the integrative vomiting center and medullary chemoreceptor trigger zone of the midbrain . |
Targets
| Target | Organism | Actions |
|---|---|---|
| Histamine H1 receptor | Humans | antagonist |
| Muscarinic acetylcholine receptor M2 | Humans | antagonist |
ADME / PK
| Absorption | Diphenhydramine is quickly absorbed after oral administration with maximum activity occurring in approximately one hour . The oral bioavailability of diphenhydramine has been documented in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration . |
|---|---|
| Half-life | The elimination half-life ranges from 2.4-9.3 hours in healthy adults . The terminal elimination half-life is prolonged in liver cirrhosis . |
| Protein binding | Some prescribing information records the protein binding of diphenhydramine as approximately 78% while others have suggested the medication is about 80 to 85% bound to plasma proteins. |
| Metabolism | Diphenhydramine undergoes rapid and extensive first-pass metabolism . In particular, two successive N-demethylations occur wherein diphenhydramine is demethylated to N-desmethyldiphenhydramine (the N-desmethyl metabolite) and then this metabolite is itself demethylated to N,N-didesmethyldiphenhydramine (the N,N-didesmethyl metabolite) . Subsequently, acetyl metabolites like N-acetyl-N-desmethyldiphenhydramine are generated via the amine moiety of the N,N-didesmethyl metabolite . Additionally, the N,N-didesmethyl metabolite also undergoes some oxidation to generate the diphenylmethoxyacetic acid metabolite as well . The remaining percentage of a dose of administered diphenhydramine is excreted unchanged . The metabolites are further conjugated with glycine and glutamine and excreted in urine . Moreover, studies have determined that a variety of cytochrome P450 isoenzymes are involved in the N-demethylation that characterizes the primary metabolic pathway of diphenhydramine, including CYP2D6, CYP1A2, CYP2C9, and CYP2C19 . In particular, CYP2D6 demonstrates higher affinity catalysis with the diphenhydramine substrate than the other isoenzymes identified . Consequently, inducers or inhibitors of these such CYP enzymes may potentially affect the serum concentration and incidence and/or severity of adverse effects associated with exposure to diphenhydramine . |
| Route of elimination | The metabolites of diphenhydramine are conjugated with glycine and glutamine and excreted in urine . Only about 1% of a single dose is excreted unchanged in urine . The medication is ultimately eliminated by the kidneys slowly, mainly as inactive metabolites . |
| Volume of distribution | Diphenhydramine is widely distributed throughout the body, including the CNS . Following a 50 mg oral dose of diphenhydramine, the volume of distribution is in the range of 3.3 - 6.8 l/kg . |
| Clearance | Values for plasma clearance of a 50 mg oral dose of diphenhydramine has been documented as lying in the range of 600-1300 ml/min . |
Formulation & handling
- Oral formulations may require solubilization strategies due to low aqueous solubility and moderate lipophilicity.
- Parenteral solutions need appropriate solvents and pH control to maintain solubility and prevent precipitation.
- Topical products leverage the lipophilic nature of the API for dermal penetration and generally have fewer stability constraints than aqueous oral liquids.
Regulatory status
| Lifecycle | The API’s key U.S. patents expired in 2022, indicating that the product is now in a post‑exclusivity phase. With current marketing limited to the US and Canada, the asset sits in a mature stage of its lifecycle with established generic entry likely. |
|---|
| Markets | US, Canada |
|---|
Supply Chain
| Supply chain summary | Diphenhydramine originated with a single innovator but is now supplied entirely through a broad network of repackagers and generic manufacturers. Branded and private‑label products are widely established in the US and Canada, with no meaningful originator exclusivity remaining. The listed formulation‑related patents expired in 2022, aligning with the mature generic competition already present across the market. |
|---|
Safety
| Toxicity | Overdose is expected to result in effects similar to the adverse effects that are ordinarily associated with the use of diphenhydramine, including drowsiness, hyperpyrexia, and anticholinergic effects, among others . Additional symptoms during overdose may include mydriasis, fever, flushing, agitation, tremor, dystonic reactions, hallucinations and ECG changes . Large overdose may cause rhabdomyolysis, convulsions, delirium, toxic psychosis, arrhythmias, coma and cardiovascular collapse . Moreover, with higher doses, and particularly in children, symptoms of CNS excitation including hallucinations and convulsions may appear; with massive doses, coma or cardiovascular collapse may follow . Although diphenhydramine has been in widespread use for many years without ill consequence, it is known to cross the placenta and has been detected in breast milk . This medication should therefore only be used when the potential benefit of treatment to the mother exceeds any possible hazards to the developing fetus or suckling infant . Pharmacokinetic studies indicate no major differences in the distribution or elimination of diphenhydramine compared to younger adults . Nevertheless, diphenhydramine should be used with caution in the elderly, who are more likely to experience adverse effects . Avoid use in elderly patients with confusion . The results of a review on the use of diphenhydramine in renal failure suggest that in moderate to severe renal failure, the dose interval should be extended by a period dependent on Glomerular filtration rate (GFR) . After intravenous administration of 0.8 mg/kg diphenhydramine, a prolonged half-life was noted in patients with chronic liver disease which correlated with the severity of the disease . However, the mean plasma clearance and apparent volume of distribution were not significantly affected . LD<sub>50</sub>=500 mg/kg (orally in rats). Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular dysrhythmias, coma and death. |
|---|
- Significant overdose may elicit pronounced anticholinergic and CNS toxicity, including agitation, hallucinations, tremor, dystonic reactions, ECG abnormalities, arrhythmias, and risk of coma or cardiovascular collapse
- Prolonged half‑life is reported in chronic liver disease
- Altered clearance profiles may also occur in moderate to severe renal impairment
US Drug Master File (USDMF)
A US Drug Master File (USDMF) is a confidential document submitted to the U.S. Food and Drug Administration (FDA) that provides detailed information about the manufacturing process of an Active Pharmaceutical Ingredient (API) or a finished pharmaceutical product. This document includes comprehensive details such as chemical properties, manufacturing facilities, production processes, packaging specifications, storage conditions, and more.
The USDMF ensures that proprietary information remains protected while allowing the FDA to review the data as part of drug approval processes. Unlike other types of DMFs used in different regions, the USDMF is specifically designed to meet the regulatory requirements set by the FDA, ensuring compliance with U.S. standards.
Diphenhydramine is a type of Antihistamines
Antihistamines are a vital subcategory of pharmaceutical Active Pharmaceutical Ingredients (APIs) widely used in the treatment of allergies and allergic reactions. These compounds work by blocking the action of histamines, which are responsible for triggering allergic symptoms such as itching, sneezing, runny nose, and watery eyes.
Antihistamines can be classified into two main categories: first-generation and second-generation antihistamines. First-generation antihistamines, such as diphenhydramine and chlorpheniramine, have been in use for several decades. They are effective in relieving allergy symptoms but are associated with drowsiness and other side effects due to their ability to cross the blood-brain barrier.
On the other hand, second-generation antihistamines, including cetirizine, loratadine, and fexofenadine, offer similar allergy relief with fewer sedative effects. These newer antihistamines are preferred for their improved safety profiles, making them suitable for use during the day without causing significant drowsiness.
Antihistamines are available in various forms, including tablets, capsules, syrups, and topical creams. They are extensively used to manage conditions such as hay fever, hives, allergic rhinitis, and insect bites. Moreover, antihistamines may also be combined with decongestants or other medications to provide relief from nasal congestion and sinus symptoms.
As pharmaceutical APIs, antihistamines are produced through meticulous synthesis and manufacturing processes, adhering to strict quality standards. These APIs serve as the active components in various branded and generic pharmaceutical formulations, making them crucial in the pharmaceutical industry's production of allergy medications.
In conclusion, antihistamines are a significant subcategory of pharmaceutical APIs widely used for alleviating allergy symptoms. Their classification into first- and second-generation antihistamines offers options based on efficacy and sedative effects. By blocking histamines, antihistamines provide relief from common allergic reactions, making them essential in the development of effective allergy medications.
Diphenhydramine (Antihistamines), classified under Central Nervous System Agents
Central Nervous System (CNS) Agents are a crucial category of pharmaceutical Active Pharmaceutical Ingredients (APIs) that specifically target the central nervous system. The CNS encompasses the brain and spinal cord, playing a vital role in regulating and controlling various bodily functions, including cognition, movement, emotions, and sensory perception. These agents are designed to interact with specific receptors, enzymes, or ion channels within the CNS to modulate neural activity and restore normal functioning.
CNS agents comprise a diverse range of pharmaceutical APIs, including analgesics, anesthetics, antipsychotics, sedatives, hypnotics, anti-epileptics, and antidepressants. Each subcategory addresses distinct neurological disorders and conditions. For instance, analgesics alleviate pain by targeting receptors in the brain and spinal cord, while antipsychotics are employed to manage psychosis symptoms in mental illnesses such as schizophrenia.
The development of CNS agents involves rigorous research, molecular modeling, and extensive clinical trials to ensure safety, efficacy, and specific target engagement. Pharmaceutical companies invest significant resources in identifying novel drug targets, synthesizing new compounds, and optimizing their pharmacological properties. These agents undergo rigorous regulatory evaluations and must adhere to stringent quality standards and guidelines.
Given the prevalence of CNS disorders globally, the market demand for effective CNS agents is substantial. The development of innovative CNS APIs not only improves patient outcomes but also provides valuable commercial opportunities for pharmaceutical companies. Continued advancements in CNS agent research and development hold the promise of groundbreaking therapies that can improve the quality of life for individuals affected by neurological conditions.
Diphenhydramine API manufacturers & distributors
Compare qualified Diphenhydramine API suppliers worldwide. We currently have 14 companies offering Diphenhydramine API, with manufacturing taking place in 8 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Albemarle | Producer | United States | United States | CoA, USDMF | 17 products |
| Apollo Healthcare Resourc... | Distributor | Singapore | Singapore | BSE/TSE, CEP, CoA, EDMF/ASMF, FDA, GMP, ISO9001, JDMF, KDMF, MSDS, USDMF, WC | 200 products |
| Aurora Industry Co., Ltd | Distributor | China | China | BSE/TSE, CEP, CoA, GMP, HALAL, ISO14001, ISO9001, Kosher, MSDS | 250 products |
| AXXO GmbH | Distributor | Germany | World | CEP, CoA, GMP, GDP, MSDS, USDMF | 243 products |
| Chr. Olesen Group | Distributor | Denmark | India | CEP, CoA, GMP, MSDS | 252 products |
| Kongo Chemical | Producer | Japan | Japan | CoA, USDMF | 5 products |
| LGM Pharma | Distributor | United States | World | BSE/TSE, CEP, CoA, GMP, MSDS, USDMF | 441 products |
| M2i Life | Producer | France | France | CoA | 1 products |
| Medinex Labs. | Producer | India | India | CoA, GMP, WC | 8 products |
| Pharm Rx Chemical Corp | Distributor | United States | China | BSE/TSE, CoA, GMP, MSDS, USDMF | 166 products |
| Recordati S.p.A. | Producer | Italy | Italy | CEP, CoA, FDA, USDMF | 18 products |
| Rochem International, Inc... | Distributor | United States | United States | BSE/TSE, CoA, GMP, ISO9001, MSDS | 144 products |
| Shanghai Wonder Pharma | Producer | China | China | CoA, WC | 5 products |
| Wanbury | Producer | India | India | CEP, CoA, FDA, GMP, USDMF, WC | 15 products |
When sending a request, specify which Diphenhydramine API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
Use the list above to find high-quality Diphenhydramine API suppliers. For example, you can select GMP, FDA or ISO certified suppliers. Visit our help page to learn more about sourcing APIs via Pharmaoffer.
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