Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Ultrason Sonochem. 2024 Jul;107:106946. doi: 10.1016/j.ultsonch.2024.106946. 
Epub 2024 Jun 6.

Facilitating polymorphic crystallization of HMX through ultrasound and trace 
additive assistance.

Li J(1), Li S(2), Huang S(2), Xu J(2), Yan Q(3), Jin S(4), Liu Y(5).

Author information:
(1)Institute of Chemical Materials, China Academy of Engineering and Physics, 
Mian Yang 621900, China; School of Materials Science and Engineering, Beijing 
Institute of Technology, Beijing 100083, China.
(2)Institute of Chemical Materials, China Academy of Engineering and Physics, 
Mian Yang 621900, China.
(3)Science and Technology on Combustion, Internal Flow and Thermo-structure 
Laboratory, Northwestern Polytechnical University, Xi'an 710072, China.
(4)School of Materials Science and Engineering, Beijing Institute of Technology, 
Beijing 100083, China. Electronic address: jinshaohua@bit.edu.cn.
(5)Institute of Chemical Materials, China Academy of Engineering and Physics, 
Mian Yang 621900, China. Electronic address: new615@163.com.

Low sensitivity octahydro-1,3,4,7-tetranitro-1,3,5,7-tetrazocine (HMX) has 
garnered significant attention from researchers due to its reduced shock 
sensitivity. However, the crystallization process poses challenges due to the 
high solidity and viscosity of the metastable α phase. Despite efforts to 
address this with additional energy sources like ultrasonic irradiation, 
prolonged exposure duration often results in small particle sizes, hindering the 
production of HMX with a consistent particle size distribution, thus limiting 
its applicability. To overcome these challenges, a method combining ultrasonic 
irradiation and trace H+ additive was proposed and investigated for their impact 
on the polymorphic transformation of HMX. The H+ additive was found to modify 
barriers, thus there was a lack of competitive driving force for the nucleation 
or growth of the metastable α form, thereby shortening the transformation 
pathway and duration. Moreover, the H+ additive significantly accelerated the 
nucleation rate of the β form (67.7 orders of magnitude faster with 0.10 wt ‰ 
H+) and the growth rate of β form HMX (5.8 orders of magnitude faster with 
0.10 wt ‰ H+). While H+ additive alone was insufficient to induce spontaneous 
nucleation of the β form, combining it with short-duration ultrasonic 
irradiation further promoted β nucleation and shortened the polymorphic 
transformation duration (almost 20 orders of magnitude shorter). This rational 
approach led to effective control of the transformation process. The resulting 
low sensitivity HMX crystals exhibited varying mean sizes ranging from 20 to 
340 μm, with purity exceeding 99.6 %, an apparent density greater than 
1.8994 g/cm3, and few internal defects, fully meeting the requirements of 
low-sensitivity HMX, thus significantly expanding its potential applications. 
Our study sheds light on the mechanisms governing HMX polymorphic transformation 
in the presence of additives and ultrasonic irradiation, offering guidance for 
the rational control of this complex transformation.

Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.

DOI: 10.1016/j.ultsonch.2024.106946
PMCID: PMC11187238
PMID: 38852536

Conflict of interest statement: Declaration of competing interest The authors 
declare that they have no known competing financial interests or personal 
relationships that could have appeared to influence the work reported in this 
paper.


2. Hypertension. 2024 Jun;81(6):1190-1193. doi:
10.1161/HYPERTENSIONAHA.124.21368.  Epub 2024 May 15.

Short-Lived Active Prorenin: Precursor of So-Called Native Prorenin.

Schalekamp MADH(1), Deinum J(2), Danser AHJ(1).

Author information:
(1)Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands 
(M.A.D.H.S., A.H.J.D.).
(2)Department of Internal Medicine, Radboud University MC, Nijmegen, The 
Netherlands (J.D.).

The enzymatic activity of the aspartic protease, renin, is critical for its 
function in blood pressure regulation and sodium homeostasis. Incubation of 
so-called native prorenin at low pH leads to its activation. After binding to 
transition-state mimicking renin inhibitors at neutral pH, prorenin attains the 
active conformation, as indicated by immunosorbent assay using monoclonal 
antibodies specific for epitopes of the prosegment or the renin body. A 
comparison of immunosorbent assay with enzyme-kinetic assay revealed the 
intermediary steps of prorenin auto-activation/inactivation. The kinetically 
identified intermediary steps of activation/inactivation correspond with the 
published crystal structures of free renin, free prorenin, and renin in complex 
with inhibitors. Both renin and activated prorenin exist in 2 forms, α and β. 
The α form is active, and the α/β quantity ratio is 2.5. The kidney produces 
renin and prorenin, while the ovarium, placenta, and eye produce inactive 
prorenin. The production of renin by these organs has never been demonstrated. 
We propose that the so-called native prorenin in extracellular fluid, including 
the circulation, is derived, at least partly, from short-lived active prorenin. 
Its potential paracrine function is discussed.

DOI: 10.1161/HYPERTENSIONAHA.124.21368
PMCID: PMC11095897
PMID: 38748765 [Indexed for MEDLINE]

Conflict of interest statement: Disclosures None.


3. Heliyon. 2024 Feb 27;10(5):e27131. doi: 10.1016/j.heliyon.2024.e27131. 
eCollection 2024 Mar 15.

Impact of crystal polymorphism of rifaximin on dissolution behavior.

Toukabri I(1), Bahri S(1), Sfar S(1), Lassoued MA(1).

Author information:
(1)Laboratory of Chemical, Galenic and Pharmacological Development of Medicines 
(LR12ES09), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, 
Tunisia.

INTRODUCTION: Rifaximin is an intestinal antiseptic which has five (pseudo) 
polymorphs α, β, γ, δ and ε. These last (pseudo)polymorphs have different 
physicochemical properties. The objective of the study is to assess the impact 
of rifaximin polymorphism on its dissolution rate which could affect its 
bioavailability.
MATERIAL AND METHODS: The analytical validation of dissolution assay method by 
UV-Visible spectrophotometry was carried out according to ICH Q2. The 
physicochemical characterization (solubility test, FTIR, DSC, XRD) was carried 
out on four active pharmaceutical ingredient (MP1, MP2, MP3, MP4). MP1 and MP2 
were used by the manufacturer of generic brand 1 (G1) and MP3 and MP4 were used 
by the manufacturer of generic brand 2 (G2). The comparative in-vitro 
dissolution study was carried out on the leader brand (P), G1 and G2.
RESULTS: The four MPs were analyzed by XRD. The results of analysis showed that 
MP1 and MP4 were a mixture of α form and amorphous form. MP2 had an amorphous 
form and MP3 had a crystalline form β. The spectra of FTIR showed that the four 
MP had characteristics bands of rifaximin in the domain 4000-400 cm-1. The 
differences between the spectra of the four MPs were observed among the 
amorphous form (MP2), around the region 1800 to 1820 cm-1 which is attributed to 
the vibration of the CO group. An additional difference observed among the 
amorphous form (MP2) is around the region 1400 cm-1 which is attributed to the 
banding OH. The thermograms of MP1, MP2 and MP4 showed endothermic peaks which 
are probably attributed to the departure of water which indicate that MP1, MP2 
and MP4 are pseudopolymoph (hydrate). For the four MPs, probably the melting 
points are interrupted by the phenomenon of phase transformations 
(Crystallization) which are reflected by exothermic peaks around 
200°C-250 °C.Our results showed that the crystalline polymorphism of rifaximin 
influences its solubility. According to the results of the solubility test, the 
β crystal form of rifaximin (MP3) had the lowest solubility (3.47 μg/ml). MP2 
had the highest solubility (8.35 μg/ml) and MP1 and MP4 had intermediate 
solubilities (5.47 μg/ml and 6.74 μg/ml). Comparative in vitro dissolution 
results showed that the dissolution profile of P was not similar to that of G1 
and G2 (% dissolution (P)30min = 60%; % dissolution (G1) 30 min = 100% and % 
dissolution (G2) 30 min = 115%; f1(P versus G1) = 44; f1(P versus G2) = 61) in 
M1, while G1 and G2 had comparatively similar dissolution profiles (% 
dissolution (G1) 30 min = 100%; % dissolution (G1) 30 min = 110%; f1 (G1 versus 
G2) = 14) in M1.
CONCLUSION: This study highlighted the impact of rifaximin polymorphism on its 
physico-chemical properties (crystal structure, thermal behavior, solubility) 
and on its dissolution behavior which could affect the rifaximin 
bioavailability.

© 2024 Published by Elsevier Ltd.

DOI: 10.1016/j.heliyon.2024.e27131
PMCID: PMC10915558
PMID: 38449665

Conflict of interest statement: The authors declare that they have no known 
competing financial interests or personal relationships that could have appeared 
to influence the work reported in this paper.


4. RSC Adv. 2024 Jan 30;14(6):4129-4141. doi: 10.1039/d3ra08481g. eCollection
2024  Jan 23.

Quantification of crystallinity during indomethacin crystalline transformation 
from α- to γ-polymorphic forms and of the thermodynamic contribution to 
dissolution in aqueous buffer and solutions of solubilizer.

Hasegawa K(1), Goto S(1), Kataoka H(1), Chatani H(1), Kinoshita T(1), Yokoyama 
H(1), Tsuchida T(1).

Author information:
(1)Faculty of Pharmaceutical Sciences, Tokyo University of Science 2641 
Yamazaki, Noda Chiba 278-8510 Japan s.510@rs.tus.ac.jp.

The thermodynamic properties and dissolution of indomethacin (INM) were analyzed 
as models for poorly water-soluble drugs. Physical mixtures of the most stable 
γ-form and metastable α-form of INM at various proportions were prepared, and 
their individual signal intensities proportional to their mole fractions were 
observed using X-ray powder diffraction and Fourier transform infrared 
spectrometry at standard temperature. The endothermic signals of the α-form, 
with a melting point of 426 K, and that of the γ-form, with a melting point of 
433 K, were obtained by differential scanning calorimetry (DSC). Furthermore, an 
exothermic DSC peak of the α/γ-phase transition at approximately 428 K was 
obtained. As we computed the melting entropy of the α-form and that of its 
transformation, the frequency of the transition was quantitatively determined, 
which indicated the maximum of the α/γ-phase transition at an α-form proportion 
of 68%. Subsequently, the thermodynamic contributions of the α- and γ-forms were 
analyzed using a Van't Hoff plot for solubility in aqueous solutions at pH 6.8. 
The dissolution enthalpies for α- and γ-forms were 28.2 and 31.2 kJ mol-1, 
respectively, which are in agreement with the quantitative contribution 
predicted by the product of the temperature and melting entropy. The 
contribution of melting entropy was conserved in different dissolution processes 
with aqueous solvents containing lidocaine, diltiazem, l-carnosine, and 
aspartame as solubilizers; their γ-form Setschenow coefficients were -39.6, 
+82.9, -17.3, and +23.2, whereas those of the α-form were -39.7, +80.4, -16.7, 
and +22.7, respectively. We conclude that the dissolution ability of the solid 
state and solubilizers indicate their additivity independently.

This journal is © The Royal Society of Chemistry.

DOI: 10.1039/d3ra08481g
PMCID: PMC10825737
PMID: 38292264

Conflict of interest statement: There are no conflicts to declare.


5. Eur J Pharm Sci. 2024 Jan 1;192:106650. doi: 10.1016/j.ejps.2023.106650. Epub 
2023 Nov 22.

The use of polymorphic state modifiers in solid lipid microparticles: The role 
of structural modifications on drug release performance.

Bertoni S(1), Simone E(2), Sangiorgi S(1), Albertini B(3), Passerini N(1).

Author information:
(1)Department of Pharmacy and Biotechnology, University of Bologna, Via S. 
Donato 19/2, Bologna 40127, Italy.
(2)Department of Applied Science and Technology, Politecnico di Torino, Torino 
10129, Italy.
(3)Department of Pharmacy and Biotechnology, University of Bologna, Via S. 
Donato 19/2, Bologna 40127, Italy. Electronic address: 
beatrice.albertini@unibo.it.

This study investigates the correlation between the structural and release 
properties of solid lipid microparticles (MPs) of tristearin containing 5 % w/w 
of four different liquid additives used as crystal modifiers: isopropyl 
myristate (IM), ethyl oleate (EO), oleic acid (OA) and medium chain 
triglycerides (MCT). All additives accelerated the conversion of the unstable 
α-form of tristearin, formed after the MPs manufacturing, to the stable 
β-polymorph and the transformation was completed within 24 h (for IM and EO) or 
48 h (for OA and MCT). The kinetic of polymorphic transition at 25 °C was 
investigated by simultaneous synchrotron SAXS/WAXS and DSC analysis after 
melting and subsequent cooling of the lipid mixture. After crystallization in 
the α-phase, additives accelerate the solid-solid phase transformation to 
β-tristearin. SAXS data showed that two types of structural modifications 
occurred on MPs during storage: compaction of the crystal packing (slight 
decrease in lamellar thickness) and crystal growth (increased number of stacked 
lipid lamellae). The release behavior of a model hydrophilic drug (caffeine) at 
two different amounts (15 % and 30 %) from MPs was studied in water and 
biorelevant media simulated the gastric and intestinal environment. It was 
particularly significant that the introduction of IM, EO and MCT were able to 
prolong the drug release in water, passing from a diffusion-based Higuchi 
kinetics to a perfect zero-order kinetic. Moreover, the overall release profiles 
were higher in biorelevant media, where erosion/digestion of MPs was observed. 
After 6 months, a moderate but statistically significant change in release 
profile was observed for the MPs with IM and EO, which can be correlated with 
the time-dependent structural alterations (i.e. larger average crystallite size) 
of these formulations; while MPs with OA or MCT displayed stable release 
profiles. These findings help to understand the correlation between release 
behavior, polymorphism and supramolecular-level structural modification of lipid 
formulations containing crystal modifiers.

Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

DOI: 10.1016/j.ejps.2023.106650
PMID: 37995834 [Indexed for MEDLINE]