Warfarin Sodium Stability in Oral Formulations

Warfarin sodium is a low-dose pharmaceutical blood thinner that exists in two forms: the clathrate form and the amorphous form. In commercially available warfarin sodium oral suspension, the active pharmaceutical ingredient (API) is added in the amorphous state. This study investigates the apparent instability of the commercially available warfarin liquid oral formulation using Raman and IR spectroscopy, X-ray diffraction, differential scanning calorimetry, UV spectroscopy, and optical microscopy. Warfarin, not its sodium salt, was identified as the undissolved solid existing in the suspension. This was found to be due to the dissociation of sodium salt and the protonation of the warfarin ion in the liquid phase, which triggered the crystallization of the sparingly soluble unsalted form. The coexistence of protonated and unprotonated warfarin ions in the supernatant, as detected by Raman and UV spectroscopy, confirmed this assumption. Study of the dissolution of warfarin sodium amorphous salt and crystalline sodium clathrate in the placebo and pure water verified the results. The effect of pH and temperature on warfarin precipitation was also explored.

Comparison between 5 mg and 10 mg warfarin loading doses therapy in cardiac care unit patients at Elobied Hospital, Elobied City- Sudan

Background and objectives: Warfarin sodium therapy is usually initiated with a loading dose to reduce the time needed to reach the target international normalized ratio (INR). The right initial dose of warfarin is controversial. This study aimed to determine the best initial dose of warfarin in terms of safety and efficacy. Patients and methods: This is a prospective hospital-based study. Fifty-nine patients who were admitted to the coronary care unit with clinical indication for warfarin were assigned to use the initial dose of warfarin 5 mg or 10 mg with the target INR of 2-3. An ethical clearance was obtained from the state ministry of health. A written consent was taken from each patient. An INR was measured at baseline and then after 72 hours. The data were then collected using a data sheet including age, gender, baseline INR, initial dose of warfarin, INR after 72 hours and whether the patient developed bleeding or not. Patients on Aspirin and other non-steroidal anti-inflammatory drugs were excluded. The data were analyzed using SPSS version 18. Results: A total number of 59 patients were enrolled in the study. In this series, 59% of patients were females. The mean age of patients was 56 years. Five mg loading dose was used in 35 of patients (59%) while 10 mg was used in 24 patients (41%). The mean INR after 72 hours was 2.8 for those with the initial dose of 5 mg. For those with the initial loading dose of 10 mg the mean INR after 72 hours was 3.2. Minor bleeding occurred in three patients, two of them used the initial loading dose of 5mg and only one patient from the group of 10mg. Conclusion: From this study, it seems that 5 mg loading dose of warfarin is reasonable and cost effective; nevertheless, 10mg initial loading dose is not associated with increased risk of bleeding.

Structural Changes of Sodium Warfarin in Tablets Affecting the Dissolution Profiles and Potential Safety of Generic Substitution

At present, the risk of generic substitutions in warfarin tablets is still being discussed. The aim of this study was to assess whether API interactions with commonly used excipients may affect the safety of generic replacement of warfarin sodium tablets. These interactions were observed during an accelerated stability study, and the effect of the warfarin solid phase (crystalline/amorphous form) as well as the API particle size distribution was studied. Commercial tablets and prepared tablets containing crystalline warfarin or amorphous warfarin were used. In addition, binary mixtures of warfarin with various excipients were prepared. The structural changes before and after the stability study were monitored by dissolution test in different media, solid-state NMR spectroscopy and Raman microscopy. During the stability study, the conversion of the sodium in warfarin to its acid form was demonstrated by some excipients (e.g., calcium phosphate). This change in the solid phase of warfarin leads to significant changes in dissolution, especially with the different particle sizes of the APIs in the tablet. Thus, the choice of suitable excipients and particle sizes are critical factors influencing the safety of generic warfarin sodium tablets.

Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial

Objectives To determine whether the generic and branded warfarins used as anticoagulants in Brazil are therapeutic equivalents based on their international normalized ratio (INR) results. Methods This crossover randomized controlled trial had four periods. We used the branded Marevan and two generic versions of warfarin sodium tablets, manufactured by União Química and Teuto laboratories, all purchased from retail drugstores. Eligible participants were outpatients from an anticoagulation clinic at a university hospital in São Paulo, Brazil. They had atrial fibrillation or flutter and had been using warfarin for at least 2 months with an INR therapeutic range of 2.0–3.0. Randomization was by numbered, opaque, sealed envelopes. Healthcare personnel and outcome assessors were blinded to treatments, but patients were not. The primary outcome was the variability in the INR (ΔINR) and secondary outcomes included mean INR. We accepted formulations as equivalent if the 95% confidence interval (CI) of the comparison of ΔINR between branded and generic formulations was within the limit of ±0.49. Results One hundred patients were recruited and randomized to six sequences of treatment (four sequences with n = 17 and two sequences with n = 16). União Química generic warfarin had equivalent variability in the INR to Marevan (ΔINR +0.09 [95% CI -0.29 to +0.46], n = 84). Comparison between Teuto generic warfarin and Marevan was inconclusive (ΔINR +0.29 [95% CI -0.09 to +0.68], n = 84). Conclusions Marevan and União Química warfarin had equivalent therapeutic effectiveness and both could be confidently used for anticoagulation. The comparison between Marevan and TW was inconclusive and does not warrant a statement of equivalence. Our methods are especially important for comparing generic and branded drugs that raise concerns and may be subject of future investigations by regulatory agents. Trial registration ClinicalTrials.gov NCT02017197.

Biological Evidences of Dicoumarol: A Review

Dicoumarol, a natural anticoagulant drug chemically designated as is metabolized from coumarin in the sweet clover (Melilotus alba and Melilotus officinalis) by molds, such as Penicillium nigricans and Penicillium jensi. Coumarin (1,2-benzopyrone), the parent molecule of dicoumarol, is the simplest compound of a large class of naturally occurring phenolic substances made of fused benzene and pyrone rings . In addition, the coumarin anticoagulants, dicoumarol (Dicumarol) and its synthetic derivative warfarin sodium (Coumadin), have been shown to decrease metastases in experimental animals. Warfarin sodium, largely replacing dicoumarol therapeutically as an anticoagulant, has been used for the treatment of a variety of cancers and shown to improve tumor response rates and survival in patients with several types of cancer. However, despite numerous studies, little information has been acquired on the cellular mechanism of action of coumarin compounds in the treatment of malignancies. Possibly for this reason, the coumarin compounds have not received much attention for the treatment of cancer.