Solution-Mediated Phase Transformation of Haloperidol Mesylate in the Presence of Sodium Lauryl Sulfate

Greco, Kristyn; Bogner, Robin H.

doi:10.1208/s12249-011-9656-4

Cited by 9 publications

(4 citation statements)

References 23 publications

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“…The in vitro peak drug concentration and peak duration produced by supersaturating dosage forms are highly dependent on the drug, drug form, formulation components, and solution composition (5,(28)(29)(30)(31)(32)(33)38,39,(48)(49)(50). To bracket a range of bioavailability that could be reasonably expected from supersaturating dosage forms, two alternative assumptions were used: either (a) the duration of the peak drug concentration in vivo corresponds to the in vitro data or b) the drug concentration in vivo reaches the peak concentration observed during in vitro dissolution.…”

Section: Discussionmentioning

confidence: 99%

Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs

Kleppe

Forney-Stevens

Haskell

et al. 2015

AAPS J

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Abstract. Poorly soluble drugs are increasingly formulated into supersaturating drug delivery systems which may precipitate during oral delivery. The link between in vitro drug concentration profiles and oral bioavailability is under intense investigation. The objective of the present work was to develop closedform analytical solutions that relate in vitro concentration profiles to the amount of drug absorbed using several alternate assumptions and only six parameters. Three parameters define the key features of the in vitro drug concentration-time profile. An additional three parameters focus on physiological parameters. Absorption models were developed based on alternate assumptions; the drug concentration in the intestinal fluid: (1) peaks at the same time and concentration as in vitro, (2) peaks at the same time as in vitro, or (3) reaches the same peak concentration as in vitro. The three assumptions provide very different calculated values of bioavailability. Using Case 2 assumptions, bioavailability enhancement was found to be less than proportional to in silico examples of dissolution enhancement. Case 3 assumptions lead to bioavailability enhancements that are more than proportional to dissolution enhancements. Using Case 1 predicts drug absorption amounts that fall in between Case 2 and 3. The equations developed based on the alternate assumptions can be used to quickly evaluate the potential improvement in bioavailability due to intentional alteration of the in vitro drug concentration vs. time curve by reformulation. These equations may be useful in making decisions as to whether reformulation is expected to provide sufficient bioavailability enhancement to justify the effort.

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Section: Discussionmentioning

confidence: 99%

Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs

Kleppe

Forney-Stevens

Haskell

et al. 2015

AAPS J

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“…Experiments performed by Brewster et al included cosolvents, for example, dimethyl sulfoxide to generate supersaturation.). [17][18][19][20][21][22][23] Brewster et al 21 showed that surfactants like tocopheryl polyethylene glycol succinate and Tween 20 at concentrations above critical micelle concentration (CMC) delay SMPT (i.e., slow the rate of amorphous to crystalline conversion). Chen et al 19 reported that Tween 80 at concentrations below the CMC promoted SMPT of the free base form of an experimental drug to its chloride salt crystalline form.…”

Section: Introductionmentioning

confidence: 99%

“…20 SMPT was an order of magnitude faster in the presence of SLS than in NaTc. Greco et al 23 reported the complex effect of SLS on the SMPT of haloperidol mesylate to haloperidol free base. There was a minimum in apparent conversion rate of haloperidol mesylate at 5 mM SLS; however, the time course of SMPT increased at SLS concentrations either above or below this "critical value."…”

Section: Introductionmentioning

confidence: 99%

Biorelevant Media Slows the Solution-Mediated Phase Transformation of Amorphous Spironolactone

Kleppe

Haskell

Bogner

2018

Journal of Pharmaceutical Sciences

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Solution-mediated phase transformation (SMPT) can reduce the high drug concentration expected from amorphous formulations, eliminating the improvement in drug absorption one hoped to gain from this high energy drug state. The differences in SMPT of a supersaturating system were compared in biorelevant media (fasted state simulated intestinal fluid and fed state simulated intestinal fluid) and United States Pharmacopeia compendial medium, simulated intestinal fluid without pancreatin. Amorphous spironolactone underwent SMPT to the same hydrate of spironolactone in all 3 media which was confirmed by the decrease in dissolution rates assessed in a flow-through dissolution apparatus, as well as by the appearance of crystals on the amorphous solid surface detected by polarized light microscopy. Longer duration of supersaturation which may lead to greater in vivo oral drug absorption was found in both biorelevant media, compared to compendial (average > 90 vs. 20 min), indicating that the presence of surfactants in biorelevant media delays crystal growth. Surface profiles and polarized light micrographs suggest that (1) a significant increase in surface area due to 3D crystal formation, (2) amorphous areas remaining exposed on the surface, and (3) a lower nucleation rate are potential reasons for an elevated dissolution rate even after SMPT.

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“…During the preparation of this manuscript, Aitipamula et al have reported some aliphatic salts of haloperidol and a polymorph of the saccharinate salt . An extensive solubility study has been attempted on the mesylate salt of haloperidol at different pH as well as in the presence of surfactants . However, until now there is no report on the crystal structure of the mesylate salt.…”

Section: Introductionmentioning

confidence: 99%

Stable Crystalline Salts of Haloperidol: A Highly Water-Soluble Mesylate Salt

Rajput

2014

Crystal Growth & Design

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Haloperidol, an antipsychotic drug, was screened for new solid crystalline phases using high throughput crystallization in pursuit of solubility improvement. Due to the highly basic nature of the API, all the solid forms with acids were obtained in the form of salts. Eleven crystalline salts in the form of oxalate (1:1), benzoate (1:1), salicylate (1:1 and 1:2), 4hydroxybenzoate (1:1), 4-hydroxybenzoate ethyl acetate solvate (1:1:1), 3,4dihydroxybenzoate (1:1), 3,5-dihydroxybenzoate (1:1), mesylate (1:1), besylate (1:1), and tosylate (1:1) salt were achieved. There is an insertion of carboxylate or sulfonate anion into the hydrogen bonding pattern of haloperidol. The salts with the aliphatic carboxylic acids were found to be more prone to form salt hydrates compared with aromatic carboxylate salts. All the salts were subjected to solubility measurement in water at neutral pH. There was no direct correlation observed between the solubility of the salt and its coformer. All the salts are stable at room temperature as well as after 24 h slurry experiment except the oxalate salt, which showed an unusual phase transformation from its hydrated form to the anhydrous form. A structure−property relationship was examined to analyze the solubility behavior of the solid forms.

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Solution-Mediated Phase Transformation of Haloperidol Mesylate in the Presence of Sodium Lauryl Sulfate

Cited by 9 publications

References 23 publications

Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs

Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs

Biorelevant Media Slows the Solution-Mediated Phase Transformation of Amorphous Spironolactone

Stable Crystalline Salts of Haloperidol: A Highly Water-Soluble Mesylate Salt

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