Chlorambucil (305-03-3) Physical and Chemical Properties
Chlorambucil
Orally active aromatic nitrogen‑mustard alkylating agent supplied as an off‑white crystalline drug substance for use as an API or reference standard, requiring cytotoxic handling and controlled quality testing.
| CAS Number | 305-03-3 |
| Family | Nitrogen mustard (alkylating agent) |
| Typical Form | Powder or crystalline solid |
| Common Grades | BP, EP, USP |
Chlorambucil is an aromatic nitrogen‑mustard small molecule standardly classified as a monocarboxylic acid bearing a para‑substituted aniline functionality: the para position of a phenylbutyric acid is substituted with an N,N‑bis(2‑chloroethyl)amino moiety. Its constitution corresponds to \(\ce{C14H19Cl2NO2}\). Structurally, the molecule combines a weakly acidic carboxylic acid head group with a lipophilic aromatic spacer and two alkylating chloroethyl arms; this juxtaposition underlies both the drug‑like oral bioavailability and the electrophilic reactivity typical of nitrogen mustards.
Electronically the molecule is moderately polar (topological polar surface area 40.5 Å^2) while retaining sufficient hydrophobic surface for membrane permeability; the computed XLogP value reported is 1.7 and experimental log Kow values near 1.70 have been used in environmental partitioning estimates. The molecule is a weak acid (\(\mathrm{p}K_a \approx 5.75\)) and therefore will be partially ionized at physiological \(\mathrm{pH}\), increasing aqueous solubility of its anionic form relative to the neutral free acid. The tertiary amine is nonprotonated in the neutral form but contributes sites for alkylation following metabolic activation or direct reaction of the chloroethyl groups with nucleophiles (DNA/protein nucleophiles).
From a performance and handling perspective chlorambucil is a solid, orally active alkylating agent used as an antineoplastic and, in selected settings, as an immunosuppressant. The compound is chemically reactive toward nucleophiles (consistent with its alkylating mechanism), sensitive to light and heat, and requires controlled handling because of its mutagenic, carcinogenic and reproductive‑toxicity hazards. Common commercial grades reported for this substance include: BP, EP, USP.
Basic Physicochemical Properties
Chlorambucil is an off‑white to pale beige crystalline or granular powder with a slight odor. The substance is a solid at ambient conditions; crystalline morphologies reported include flattened needles and fine white crystals. The solid is light‑ and heat‑sensitive and should be protected from prolonged exposure to either.
Density and Solid-State Form
No experimentally established value for this property is available in the current data context.
Observed solid‑state descriptions from manufacturing and analytical reports: off‑white/slightly granular powder; flattened needles when crystallized from petroleum ether; fine white crystals. These descriptions are consistent with an anhydrous crystalline small molecule that can form distinct needle‑like crystal habits under solvent crystallization.
Melting Point
Experimental melting-point values reported in analytical and specification text include 65–69 °C (also recorded as 147 to 151 °F). Single‑value reports show 65 °C in multiple sources. Present these values as analytical ranges and single measurements: melting point ≈ 65–69 °C (147–151 °F reported in one set of data).
Solubility and Dissolution Behavior
Measured and reported solubility data are variable and solvent‑specific:
- Reported aqueous solubility: "less than 0.1 mg/mL at 72 °F" (experimental screening result).
- Reported value: 7.73e-02 g/L (equivalent numerical listing present in analytical tables).
- A pH‑dependent solubility summary: ">45.6 [ug/mL] (The mean of the results at pH 7.4)".
- Textual descriptors: "Insoluble in water ... The sodium salt is soluble in water."
- Solvent solubility of the free acid at 20 °C: soluble in 1.5 parts ethanol, 2 parts acetone, 2.5 parts chloroform and 2 parts ethyl acetate; also soluble in benzene and ether; readily soluble in acid or alkali (reflecting the carboxylic acid chemistry and formation of soluble salts).
Dissolution behavior is therefore strongly dependent on ionization state: the free acid is poorly soluble in aqueous media, whereas the salt forms (e.g., sodium salt) show markedly higher aqueous solubility. This is consistent with the \(\mathrm{p}K_a\) (~5.75) and the common pharmaceutical strategy of using salt forms or formulation excipients to increase aqueous availability for oral tablets.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
Chlorambucil is a monocarboxylic acid (para‑substituted phenylbutyric acid). The reported dissociation constant is \(\mathrm{p}K_a = 5.75\). At neutral physiological \(\mathrm{pH}\) the compound will exist as a mixture of neutral and anionic species, with the anionic (deprotonated) form favored above the \(\mathrm{p}K_a\). Salt formation (e.g., sodium salt) markedly increases aqueous solubility and also affects the hydrolysis profile and handling characteristics.
Reactivity and Stability
Reactivity profile: - Functionally an alkylating agent: the two 2‑chloroethyl arms are electrophilic and can react with nucleophiles including DNA bases and protein side chains; this underpins the pharmacological activity (DNA alkylation and crosslinking) and toxicological hazards (mutagenicity, carcinogenicity). - Aqueous hydrolysis: aqueous solutions of the sodium salt undergo alkali‑catalyzed hydrolysis to the hydroxyl form under strongly basic conditions (example reported: reaction requiring ~30 minutes at 37 °C and pH 11.5). Little hydrolysis is observed at low temperature (no appreciable hydrolysis within 24 hours at 5 °C for the sodium salt under the conditions reported). - Environmental/abiotic hydrolysis: an experimental neutral hydrolysis rate constant corresponding to a half‑life near 1.7 hours at 25 °C is reported in aqueous conditions, indicating relatively rapid hydrolysis under certain conditions. - Stability: substance is sensitive to light and heat. Upon decomposition by heating, vapors or fumes containing hydrogen chloride and nitrogen oxides can be released; appropriate local exhaust and thermal controls are therefore required.
Implications for formulation and storage: use of low‑temperature storage, protection from light, and avoidance of strongly basic aqueous media during long‑term handling or storage is advised to minimize hydrolytic degradation and preserve assay integrity.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: \(\ce{C14H19Cl2NO2}\).
- Molecular weight: 304.2 (reported computed value).
- Exact / monoisotopic mass: 303.0792842 (reported).
Other computed parameters: heavy atom count 19; formal charge 0; molecular complexity 250.
LogP and Structural Features
- Computed XLogP (reported): 1.7.
- Experimental/derived log Kow entries reported as "log Kow = 1.70 at pH 7.4" in some environmental calculations; alternative literature entries include another reported value of 3.9 (listed as an additional reported logP figure).
- Topological polar surface area (TPSA): 40.5.
- Hydrogen‑bond donors: 1; hydrogen‑bond acceptors: 3.
- Rotatable bond count: 9.
The combination of modest logP and moderate TPSA is consistent with oral absorption (rapid GI absorption reported clinically) while the presence of multiple rotatable bonds and the tertiary amine/carboxylate motif determine conformational flexibility and salt/formulation behavior.
Structural Identifiers (SMILES, InChI)
- SMILES:
C1=CC(=CC=C1CCCC(=O)O)N(CCCl)CCCl - InChI:
InChI=1S/C14H19Cl2NO2/c15-8-10-17(11-9-16)13-6-4-12(5-7-13)2-1-3-14(18)19/h4-7H,1-3,8-11H2,(H,18,19) - InChIKey:
JCKYGMPEJWAADB-UHFFFAOYSA-N
(Identifiers are provided verbatim as structural keys and text identifiers for analytical and informatics use.)
Identifiers and Synonyms
Registry Numbers and Codes
- CAS: 305-03-3
- EC number: 206-162-0
- UNII: 18D0SL7309
- NSC numbers reported: 756674 and 3088
- ATC code: L01AA02
- Additional repository identifiers and registry codes exist in analytical and pharmacological inventories and may be used for procurement and regulatory cross‑referencing.
Synonyms and Brand-Independent Names
Common synonyms and INN/BAN style names reported include (selection from controlled lists): chlorambucil; 4‑[4‑[bis(2‑chloroethyl)amino]phenyl]butanoic acid; 4‑(bis(2‑chloroethyl)amino)benzenebutanoic acid; Leukeran; Amboclorin; Ambochlorin; Lympholysin; NSC‑3088. Multiple alternate systematic and trivial synonyms exist in pharmacopeial and chemical supplier nomenclature.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Chlorambucil is used clinically as an orally administered antineoplastic alkylating agent. It functions as a DNA‑alkylating agent that can form mono‑adducts and interstrand crosslinks, thereby inhibiting DNA replication and triggering cytotoxicity in proliferating cells. It is applied primarily in palliative and disease‑modifying regimens for selected hematologic malignancies and certain immune‑mediated disorders where slow‑acting alkylation is therapeutically appropriate. Clinically relevant attributes include rapid oral absorption, extensive plasma protein binding, and hepatic metabolism to active bifunctional metabolites.
Formulation and Development Contexts
Typical commercial and pharmacopeial presentations include oral solid formulations (tablets) containing 2 mg active ingredient; bulk powder grades are used to formulate tablets. The free acid is the typical active‑pharmaceutical ingredient, with salt forms (e.g., sodium salt) employed when increased aqueous solubility or different handling properties are required during formulation. Formulation design must account for light/heat sensitivity, low intrinsic aqueous solubility of the free acid, and the compound's reactivity as an alkylator; containment and contamination control during manufacturing are required due to toxicity.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical commercial/pharmacopeial grade labels reported for chlorambucil include: BP, EP, USP. In practice the following qualitative grade classes are encountered: - Pharmaceutical (pharmacopeial) grade for finished drug product manufacture. - Analytical reference standards for assay, stability, and method development. - Technical/chemical supply grades for research and non‑clinical use.
General Quality Attributes (Qualitative Description)
Quality attributes of interest for procurement and QC include: - Assay of active substance (pharmacopeial monographs specify identity and assay criteria in supplied standards). - Appearance and crystallinity (off‑white to pale beige crystalline powder). - Residual solvents and heavy‑metal limits appropriate to the intended use (analytical or pharmaceutical). - Moisture content, particle size distribution and polymorphic form, which can affect dissolution rate for the free acid. - Since chlorambucil is an alkylator and toxic, vendors typically supply material with accompanying certificates of analysis and controlled packaging; specific numerical impurity limits or assay ranges reported in manufacturing records should be consulted in product documentation.
If a product‑specific specification is required, refer to the manufacturer’s certificate of analysis and pharmacopeial monograph applicable to the chosen grade.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Chlorambucil is an alkylating cytotoxic compound with significant systemic toxicity potential. Key toxicological points: - Mechanism‑related hazards: ability to alkylate DNA and form crosslinks; mutagenic and carcinogenic properties associated with the alkylating function. - Reproductive and developmental toxicity potential; risks of infertility and teratogenicity are documented. - Hematologic toxicity is dose‑limiting in therapeutic use (bone marrow suppression, leukopenia, thrombocytopenia, anemia). - Acute exposure can produce gastrointestinal, neurologic and systemic effects; chronic and high‑dose exposures are associated with increased risks of secondary malignancies. - Protein binding is high (~99%), which influences distribution, clearance and potential drug interactions.
Occupational exposure routes: dermal contact, inhalation of dusts, and accidental ingestion. Clinical handling requires strict containment and specialist medical supervision when administered to patients.
For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
Storage and Handling Guidelines
General storage and handling recommendations derived from formulation and safety information: - Storage: protect from light and heat; store in tight, light‑resistant containers under refrigerated conditions (recommended 2 to 8 °C) where specified by product labeling. - Handling: perform weighing, compounding and dispensing in contained environments (biological safety cabinet or dedicated containment hood) with appropriate local exhaust and high‑efficiency filtration; use double‑gloving and impermeable gowning; splash goggles or face shield for liquid handling. - Respiratory protection: where powders or aerosols may be generated, use a NIOSH‑approved respirator with appropriate cartridges and HEPA filtration as an adjunct to engineering controls. - Spill and cleanup: treat spills as hazardous pharmaceutical contamination; use dedicated spill kits, wet cleaning with suitable decontaminants and containment of waste in sealed hazardous‑waste containers; avoid dry sweeping and uncontrolled vacuuming without HEPA filtration. - Disposal: dispose of contaminated materials and expired product via licensed hazardous‑waste routes in accordance with applicable national and local regulations; do not dispose via normal municipal waste streams.
Emergency and medical considerations: immediate decontamination for skin/eye contact, removal from exposure and prompt medical assessment for ingestion or significant inhalation exposure. Occupational medical surveillance and training are recommended for personnel routinely handling the compound.
For operations involving formulation, manufacturing, or clinical preparation, follow institutional hazardous‑drug handling procedures and the specific SDS provided with the material.
