Polymorphism of Alprazolam (Xanax): a review of its crystalline phases and identification, crystallographic characterization, and crystal structure of a new polymorph (form III)

A new polymorphic form of Alprazolam (Xanax), 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo-[4,3-alpha][1,4]benzodiazepine, C(17)H(13)ClN(4), has been investigated by means of X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and differential scanning calorimetry (DSC). This polymorphic form (form III) was obtained during DSC experiments after the exothermic recrystallization of the melt of form I. The crystal unit cell dimensions for form III were determined from diffractometer methods. The monoclinic unit cell found for this polymorph using XRPD after indexing the powder diffractogram was confirmed by the cell parameters obtained from single crystal X-ray diffractometry on a crystal isolated from the DSC pans. The single crystal unit cell parameters are: a = 28.929(9), b = 13.844(8), c = 7.361(3) angstroms, beta = 92.82(3) degrees , V = 2944(2) angstroms(3), Z = 8, space group P2(1) (No.4), Dx = 1.393 Mg/m(3). The structure obtained from single crystal X-ray diffraction was used as initial model for Rietveld refinement on the powder diffraction data of form III. The temperature phase transformations of alprazolam were also studied using high temperature XRPD. A review of the different phases available in the Powder Diffraction File (PDF) database for this drug is described bringing some clarification and corrections.     

阿普唑仑片中阿普唑仑的HPLC测定

目的:建立用HPLC法测定阿普唑仑片中阿普唑仑含量的方法。方法:LiChrospher C18柱(4．6 mm×250 mm,5μm),以磷酸盐缓冲液(取磷酸二氢钾16 g和磷酸氢二钾4 g,加水溶解并稀释至2 000 ml,用磷酸调节pH至6．0±0．1)-乙腈(60: 40)为流动相,检测波长254 nm,流速1．0 ml·min-1。结果:线性范围1-55μg·ml-1(r=0．999 8),阿普唑仑片中阿普唑仑平均回收率为100．1％,RSD0．9％。结论:本法灵敏、快速、准确,能有效控制产品的含量。     

Clevidipine (the Medicines Company)

The Medicines Company (under license from AstraZeneca) is developing clevidipine, a short-acting dihydropyridine calcium antagonist, for the potential treatment of peri-operative hypertension. By 1997, the compound was undergoing phase II clinical evaluation by the original developer, AstraZeneca. By March 2002, The Medicines Company was conducting phase III clinical trials.     

Alprazolam: an antidepressant? Alprazolam, desipramine, and an alprazolam-desipramine combination in the treatment of adult depressed outpatients

The antidepressant efficacy of alprazolam (ALP) was tested in a double-blind controlled comparison with desipramine (DMI) and an ALP-DMI combination in outpatients diagnosed with major depressive disorder by Research Diagnostic Criteria (90% met criteria for endogenous subtype). Following a placebo period of at least 1 week, subjects who continued to meet severity criteria defined by Hamilton Depression Rating Scale (HDRS) scores were administered oral doses of the active medication (N = 79), in a dose ratio of 1 mg ALP:50 mg DMI:1 mg ALP + 50 mg DMI. Treatment continued for 6 weeks, and all subjects who completed at least 2 weeks (N = 69) were included in endpoint analyses. Following the placebo baseline, symptoms were rated again at day 5 and at the end of weeks 1, 2, 4, and 6. Final doses averaged 4.6 +/- 1.3 mg for the ALP group, 230 +/- 61 mg for the DMI group, and 4.6 +/- 1.2 mg ALP + 229.5 +/- 1.2 mg DMI for the combination group. The final outcome was a comparable degree of improvement at the endpoint among the three treatment groups on measures of depression (HDRS and Beck Depression Inventory), anxiety (Hamilton Anxiety Rating Scale), and global improvement (Global Assessment Scale, and Physician and Patient Global Impressions). A similar outcome was found for the subgroup of patients who completed all 6 weeks (N = 56). Endpoint analyses also showed that ALP-treated subjects responded sooner and continued to show improvement throughout the course of the study on measures of depression, anxiety, and global status. These results suggest that ALP alone is as effective as a standard tricyclic for the acute treatment of patients with major depressive disorder and that significant improvement may occur within the first week of medication. Side effect profiles were compared among treatment groups and are discussed, as are other clinical studies that have investigated ALP's potential antidepressant efficacy.     

Detection of alprazolam (Xanax) and its metabolites in urine using dual capillary column, dual nitrogen detector gas chromatography

Alprazolam (Xanax) is a fairly new, yet very popular benzodiazepine tranquilizer. In 1985, it was 6th on a nationwide list of drugs mentioned in emergency room drug poisonings. A procedure was developed that allows alprazolam and its main urinary metabolites, alpha-hydroxyalprazolam and 3-hydroxymethyl-5-methyltriazolyl chlorobenzophenone, to be detected in urine specimens. A dual capillary column, dual nitrogen detector gas chromatographic system was used for reliable identification. Improved chromatographic performance was obtained by acetylating the metabolites. Method characteristics such as linearity, reproducibility, limit of detection, and recovery were determined. The method was tested by assaying urine specimens from hospitalized patients who had been ingesting alprazolam. In most cases, alpha-hydroxyalprazolam was found in the highest concentration and separated best from endogenous urine substances. A single dose concentration-time study was performed, and the time course of alprazolam and metabolite concentrations over 48 hours was determined.     

Alprazolam abuse in Texas, 1998-2004

Alprazolam (Xanax) is used in the treatment of anxiety, depression, and panic attacks, and is subject to abuse. The objective of this study was to describe the patterns of alprazolam abuse and drug identification (ID) calls received by several poison control centers. Cases were alprazolam calls received by 6 poison control centers during 1998-2004. Of 25,954 alprazolam calls received, 42% were drug ID calls and 51% were human exposure calls, of which 18% were abuse calls. The number of drug ID calls and the number of abuse calls both increased during the 7-yr period. Male patients accounted for 54% of abuse calls and females for 66% of nonabuse calls. Adolescent patients comprised 43% of abuse calls but only 12% of nonabuse calls. Although the majority of both types of human exposures occurred at the patient's own residence, abuse exposures were more likely than other exposures to occur at school (9% vs. 1%) and public areas (6% vs. 1%). While abuse calls were less likely than nonabuse calls to have no adverse clinical effects (19% vs. 23%), they were more likely to have minor medical outcomes (60% vs. 50%). Alprazolam abuse in Texas appears to be increasing. Alprazolam abusers are more likely to be male and often adolescent. Alprazolam abuse as compared to other exposures is more likely to occur outside of the person's home. Alprazolam abuse is more likely to involve some sort of adverse medical outcome.     

Alprazolam in the treatment of obsessive symptoms

Four patients with obsessive-compulsive disorder (DSM-III and RDC) were treated in an open trial with alprazolam. Moderate to marked improvement was noted in the degree of obsessionality, anxiety with motor tension, and secondary affective changes. The mixed anxiolytic-antidepressant properties of alprazolam are theorized as the basis for the clinical remissions.     

Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action

Alprazolam, a triazolobenzodiazepine, is the first of this new class of benzodiazepine drugs to be marketed in the United States and Canada. It achieves peak serum levels in 0.7 to 2.1 hours and has a serum half-life of 12 to 15 hours. When given in the recommended daily dosage of 0.5 to 4.0 mg, it is as effective as diazepam and chlordiazepoxide as an anxiolytic agent. Its currently approved indication is for the treatment of anxiety disorders and symptoms of anxiety, including anxiety associated with depression. Although currently not approved for the treatment of depressive disorders, studies published to date have demonstrated that alprazolam compares favorably with standard tricyclic antidepressants. Also undergoing investigation is the potential role of alprazolam in the treatment of panic disorders. Alprazolam has been used in elderly patients with beneficial results and a low frequency of adverse reactions. Its primary side effect, drowsiness, is less than that produced by diazepam at comparable doses. Data on toxicity, tolerance, and withdrawal profile are limited, but alprazolam seems to be at least comparable to other benzodiazepines. Drug interaction data are also limited, and care should be exercised when prescribing alprazolam for patients taking other psychotropic drugs because of potential additive depressant effects.     

Alprazolam in the treatment of panic disorders

An open clinical trial of alprazolam therapy of patients with panic disorder or agoraphobia with panic attacks was undertaken to clarify certain issues not resolved by previous studies. These included the proportion of patients who significantly improve with alprazolam; the relative time courses for improvement in panic attacks, anticipatory anxiety, and phobic avoidance; whether successful alprazolam treatment alters vulnerability to panic with sodium lactate infusion; and what factors predict response to alprazolam in panic patients. Thirty patients meeting DSM-III criteria for panic disorder or agoraphobia with panic attacks completed a 12-week open clinical trial, and 22 were considered responders. In responders, panic attacks showed rapid improvement, whereas improvement of anticipatory anxiety and phobic avoidance was more variable. Successful alprazolam therapy appeared to block lactate vulnerability. High pretreatment Hamilton Anxiety Scale scores were associated with poor treatment response. The data suggest that alprazolam is an effective treatment for panic disorder and agoraphobia with panic attacks, and acts by directly blocking panic attacks.     

Alprazolam: Review of pharmacological,pharmacokinetic, and clinical data

Alprazolam is a recently marketed triazolobenzodiazepine. The animal pharmacological data reviewed here suggest a potent anxiolytic action. But, in addition, an antidepressant activity was revealed in clinical studies and subsequently studied in animal assays. As an extension of these activities, alprazolam also displays efficacy in panic and phobic disorders. Data relating to a wide range of pharmacological activities and pharmacokinetics of alprazolam are also reviewed.     

Comparative Study of the Abuse Liability of Alprazolam,Lorazepam, Diazepam,Methaqualone, and Placebo

Subjective effects of two benzodiazepines–alprazolam and lorazepam– were compared with two drugs of known abuse potential–diazepam and methaqualone–and placebo. This double-blind, crossover trial tested 30 casual recreational sedative users in a seminaturalistic setting. Methaqualone was more euphoriant and less sedative than the benzodiazepines. Diazepam and lorazepam were more euphoriant than placebo; alprazolam's euphoriant effect did not differ from these treatments. On other measures of abuse liability the benzodiazepines rated similarly, diazepam rating highest.