Analysis of cannabidiol (CBD) and THC in nonprescription consumer products: Implications for patients and practitioners.

PURPOSE: Cannabidiol products remains largely unregulated in the US. Unlike the Rx formulation of CBD [EpidiolexR], little information is available regarding labeling accuracy (does the product contain what the label says it does), lot to lot variability, nor long-term product stability. Understanding these properties are fundamental if these products are to be used in patients with epilepsy, where product variability of traditional AEDs has been suspected to result in inadequate seizure control. Therefore, we analyzed commercial CBD products, including oils, aqueous products (i.e., beverages), and various Other products for cannabinoid content vs label claims and stability under United States Pharmacopeia (USP) standards. METHOD: Samples were diluted and analyzed by HPLC for CBD, THC, and CBN concentrations in order to assess product label accuracy. Products with <90% of label claim CBD were denoted over-labeled, products with >110% of label claim CBD were denoted under-labeled, and products between 90% and 110% of label claim CBD were denoted appropriately labeled, per USP standards. RESULTS: Among commercial CBD Oils (n = 11), mean CBD concentration vs label claim was 91.56% [95% CI, 66.02-117.10%], although 18.18% of oils (n = 2) made nonspecific label claims of "hemp extract" in lieu of CBD. Among all oils, 36.36% (n = 4) were appropriately labeled, another 36.4% (n = 4) of all oils were under-labeled, maximum 128.3% label claim, and finally, 9.09% (n = 1) of oils were over-labeled. The remaining 18.18% (n = 2) of oils lacked specific CBD label claims, minimum of 0.3 mg CBD per 1-ml "dose". THC was detected in 54.55% (n = 6) of oils with a maximum concentration of 0.2% w/v and a minimum concentration of 0.036% w/v. Cannabinol was detectable in only 9.1% (n = 1) of products at a concentration of 0.00465% w/v. Among aqueous products (n = 21) tested, only 66.67% (n = 14) gave specific CBD label claims, with mean CBD concentration vs label claim of 59.93% [95% CI, 38.24-81.63%]. Only 7.14% (n = 1) of aqueous products with a label claim were appropriately labeled, 14.29% (n = 2) were found to be under-labeled, and 78.57% (n = 11) over-labeled. THC was detected in 23.81% (n = 5) of aqueous products tested with a maximum THC concentration of 0.0005% w/v, and a minimum concentration of 0.0002% w/v. Cannabinol was detected in 9.52% (n = 2) of aqueous products, both at a concentration of 0.0015% w/v. "Other" products (n = 7) tested ranged from chocolate bars to transdermal patches. Some 42.86% (n = 3) gave specific CBD label claims, with mean CBD concentration vs label claim of 67.01% [95% CI, 0.87-133.14%]. Among these three "Other" products with specific label claims, 33% (n = 1) was appropriately labeled, and 66.67% (n = 2) were over-labeled, with CBD concentrations vs label claim ranging from a minimum of 39.30% to a maximum of 101.99%. The remaining 57.14% (n = 5) of "Other" products tested made nonspecific CBD label claims, denoting CBD content in terms of "full spectrum hemp extract" or "activated cannabinoids". One such product was labeled with a "40-50-mg CBD" range instead of a single, specific value. Tetrahydrocannabinol was detected in 71.43% (n = 5) of Other products tested with a maximum concentration of 0.0046% w/w, and a minimum concentration of 0.0008% w/w. Cannabinol was detected in 14.3% (n = 1) of Other products at a concentration of 0.0001% w/w. CONCLUSION: We demonstrate that commercial CBD products, especially aqueous beverages, can show inconsistent labeling, vary largely from their label claims should they make them, and show lot-to-lot variability making dosing unpredictable.

Amorphous Drug-Polymer Salt with High Stability under Tropical Conditions and Fast Dissolution: The Challenging Case of Lumefantrine-PAA.

Lumefantrine (LMF), a high-mobility and easy-to-crystallize WHO drug for treating malaria, can form an amorphous salt with poly(acrylic acid) (PAA) that is remarkably stable against crystallization at high humidity and temperature and has fast dissolution rate. The amorphous salt up to 75% drug loading was synthesized under a mild slurry condition easily implemented in basic facilities for global health. Salt formation was confirmed by IR spectroscopy and the much elevated glass transition temperature. At 50% drug loading, the amorphous salt resists crystallization for at least 18 months under the highly stressful condition of 40 °C and 75% RH. In contrast, the dispersion containing neutral LMF in PVP fully crystallized in 4 d and the dispersion in HPMCAS, a weak polyelectrolyte of lower charge density than PAA, crystallized by 50% in 7 d. The amorphous salt at 50% drug loading showed much faster dissolution than crystalline LMF: In SGF, the area under the curve (AUC) was 30 times larger within the gastric emptying time (4 h); in FaSSIF, the enhancement was even larger - by 200 times. Nanodroplets were detected during the dissolution in SGF, possibly accounting for the apparent enhancement of dissolution rate. The LMF-PAA example as a challenging case, along with the previously reported clofazimine-PAA, demonstrates the general utility of amorphous drug-polymer salts to achieve high stability under tropical conditions and enhanced dissolution and bioavailability.

Amorphous Drug-Polymer Salt with High Stability under Tropical Conditions and Fast Dissolution: The Case of Clofazimine and Poly(acrylic acid).

We report that the stability of amorphous clofazimine (CFZ) against crystallization is vastly improved by salt formation with a polymer without sacrificing dissolution rate. A simple slurry method was used to produce the amorphous salt of CFZ with poly(acrylic acid) (PAA) at 75 wt % drug loading. The synthesis was performed under a mild condition suitable for thermally unstable drugs and polymers. Salt formation was confirmed by visible spectroscopy and glass temperature elevation. The amorphous salt at 75 wt % drug loading is remarkably stable against crystallization at 40 °C and 75% RH for at least 180 days. In contrast, the amorphous solid dispersion containing the un-ionized CFZ dispersed in poly(vinylpyrrolidone) crystallized in 1 week under the same condition. The high stability of the amorphous drug-polymer salt is a result of the absence of a drug-polymer crystalline structure, reduced driving force for crystallizing the free base, and reduced molecular mobility. Despite the elevated stability, the amorphous drug-polymer salt showed fast dissolution and high solution concentration in two biorelevant media (SGF and FaSSIF). Additionally, the amorphous CFZ-PAA salt has improved tabletability and powder flow relative to crystalline CFZ. The CFZ-PAA example suggests a general method to prepare amorphous drugs with high physical stability under tropical conditions and fast dissolution.

Improving Stability and Dissolution of Amorphous Clofazimine by Polymer Nano-Coating.

PURPOSE: To inhibit the surface crystallization and enhance the dissolution of the basic amorphous drug clofazimine by polymer nano-coating. METHODS: The free surface of amorphous clofazimine was coated by dip coating in an alginate solution at pH 7. The stability of the coated amorphous drug against crystallization was evaluated by X-ray diffraction and light microscopy. The effect of coating on dissolution rate was measured in simulated gastric fluid in an USP-II apparatus at 37°C. RESULTS: At pH 7, the weak base clofazimine (pKa = 8.5) is positively charged, while the weak alginic acid (pKa = 3.5) is negatively charged, allowing coating by electrostatic deposition. Coated amorphous particles remain nearly amorphous after one year under the accelerated testing condition 40°C/75% R.H. and show faster dissolution than uncoated particles. In the first hour of dissolution, coated amorphous particles dissolve 50% faster than uncoated amorphous particles, and a factor of 3 faster than crystalline particles of the same size. CONCLUSIONS: A pharmaceutically acceptable polymer, alginate, is coated on amorphous clofazimine by electrostatic deposition and effectively inhibits its surface crystallization and enhances its dissolution rate. This is the first time the nano-coating technique is applied to a basic drug using the principle of electrostatic deposition, demonstrating the generality of the approach.

Inhibiting Surface Crystallization and Improving Dissolution of Amorphous Loratadine by Dextran Sulfate Nanocoating.

Amorphous formulations provide a solution to poor solubility and slow dissolution of many drugs, but fast surface crystallization can negate their advantages. As in the case of many amorphous drugs, loratadine (LTD) shows much faster crystal growth on the free surface than in the bulk, and its surface crystallization can be inhibited by a polymer nanocoating. LTD is a weak base with a pKa of 5.25. Dextran sulfate (DTS), a pharmaceutically acceptable polymer, is deposited on amorphous LTD from coating solution at pH 3.5 at which LTD is positively charged. Zeta potential measurements support the mechanism of nanocoating by electrostatic deposition. DTS nanocoating is as good as gold coating for inhibiting surface crystallization of amorphous LTD and significantly increases its rate of dissolution. The enhanced dissolution is likely a result of improved wetting of amorphous particles by an aqueous medium. These results indicate that fast surface crystallization of amorphous LTD is enabled by high mobility of surface molecules, and an ultrathin nanocoating can immobilize surface molecules and inhibit surface crystallization. This nanocoating technique can be used to stabilize amorphous drugs prone to surface crystallization and improve their dissolution, and DTS is an effective nanocoating material for basic drugs such as LTD.

Stability of Sodium Nitroprusside and Sodium Thiosulfate 1:10 Intravenous Admixture.

PURPOSE: Thiosulfate has been shown to reduce the risk of cyanide toxicity during nitroprusside administration. Admixtures containing both agents may provide a safe and effective alternative to more expensive agents used to reduce blood pressure in the critically ill patient. This study determined the physical and chemical stability of a 1:10 nitroprusside:thiosulfate admixture, stored up to 48 hours. The economic consequences of a shift toward using thiosulfate and nitroprusside, and away from higher cost alternatives, are considered. METHODS: Seven samples of 50 mg nitroprusside and 500 mg thiosulfate were prepared and stored away from light, at room temperature, and in a refrigerator prepared in D5W and NS. Each sample was analyzed via a novel high-performance liquid chromatographic (HPLC) method at time 0, 8, 24, and 48 hours. The method was tested and passed specifications for linearity, reproducibility, and accuracy. A visual inspection by 9 licensed pharmacists was used to demonstrate physical stability. A cost evaluation comparing nitroprusside and thiosulfate to alternative agents was completed. RESULTS: The concentration of both nitroprusside and thiosulfate remain greater than 95% of the initial concentration through 48 hours. Physical compatibility was confirmed in all samples tested through 72 hours. CONCLUSION: The combination of nitroprusside and thiosulfate is chemically and physically stable as a single compounded dose for up to 48 hours when stored at room temperature and protected from light. The admixture represents an inexpensive option to other higher cost alternatives such as nicardipine or clevidipine.

Induction of inflammatory cytokines and nitric oxide in J774.2 cells and murine macrophages by lipoteichoic acid and related cell wall antigens from Staphylococcus epidermidis.

Staphylococcus epidermidis causes infections associated with medical devices including central venous catheters, orthopaedic prosthetic joints and artificial heart valves. This coagulase-negative staphylococcus produces a conventional cellular lipoteichoic acid (LTA) and also releases a short-glycerophosphate-chain-length form of LTA (previously termed lipid S) into the medium during growth. The relative pro-inflammatory activities of cellular and short-chain-length exocellular LTA were investigated in comparison with peptidoglycan and wall teichoic acid from S. epidermidis and LPS from Escherichia coli O111. The ability of these components to stimulate the production of pro-inflammatory cytokines [interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF)-alpha] and nitric oxide was investigated in a murine macrophage-like cell line (J774.2), and in peritoneal and splenic macrophages. On a weight-for-weight basis the short-chain-length exocellular LTA was the most active of the S. epidermidis products, stimulating significant amounts of each of the inflammatory cytokines and nitric oxide, although it was approximately 100-fold less active than LPS from E. coli. By comparison the full-chain-length cellular LTA and peptidoglycan were less active and the wall teichoic acid had no activity. As an exocellular product potentially released from S. epidermidis biofilms, the short-chain-length exocellular LTA may act as the prime mediator of the host inflammatory response to device-related infection by this organism and act as the Gram-positive equivalent of LPS in Gram-negative sepsis. The understanding of the role of short-chain-length exocellular LTA in Gram-positive sepsis may lead to improved treatment strategies.

Measuring free-energy difference between crystal polymorphs through eutectic melting.

We describe a method to measure the free-energy difference, DeltaG, between crystal polymorphs from their calorimetric data of eutectic melting with a common additive. The use of different additives yields DeltaG as a function of temperature. The method is suitable for crystals that chemically decompose or physically transform before melting. It applies to not only true polymorphs but also pairs of racemate and conglomerate of resolvable enantiomers. We illustrate the method with the polymorphs of glycine, d-mannitol, and tazofelone and report a new value (123 degrees C) for the enantiotropic transition temperature of alpha and gamma glycine. We show how different additives (including a liquid additive, water) can be used for different compounds. The DeltaG data thus obtained are important for structure-stability studies and controlling crystallization in polymorphic systems.