High amylose epichlorohydrin crosslinked starch excipient was examined to gain understanding of the starch polymorph changes as the crosslinking degree (CLD) increases. When the crosslinking degree is high, the sample is mostly amorphous, and the V/B ratio decreased. For this sample, “humidification” or “water soaking”, cannot overcome crystallization restraint due to the high crosslinking degree. The water soaked 20% CLD sample show some sharp, low intensity double helix 13C resonances. This sample is paracrystalline as can be seen from the collapse of the C(1) doublet to a singlet. Relaxation studies show that increasing crosslinking degree increases the amorphous content. It is also suggested that crosslinking is not homogeneous and that it is concentrated in the non‐crystalline domain. A correlation was found between the decrease in content of B‐type material and drug release kinetics. With increasing CLD, the reduction in crystalline order increases mobility, however, increasing covalent bonds in the excipient matrix reduces mobility. Differences in relaxation rate of the several overlapping resonances in the 70—80 ppm range of the 13C spectrum are pronounced and allow tentative bond assignments.
(-)-Scopolamine hydrochloride anhydrate gives crystals belonging to the orthorhombic space group P212121 and at 293(2) K: a = 7.097(2), b = 10.686(2), c = 22.623(2) Å, V = 1715.7(6) Å3, Z = 4, R(F) = 0.039, and Rw(F) = 0.053. (-)-Scopolamine hydrochloride 1.66hydrate yields crystals belonging to the tetragonal space group P43212 and at 293(2) K: a = b = 11.843(6), c = 26.211(4) Å, V = 3676(3) Å3, Z = 8, R(F) = 0.047, and Rw(F2) = 0.135. (-)-Scopolamine methobromide affords crystals belonging to the orthorhombic space group P212121 and at 293(2) K: a = 7.0403(8), b = 10.926(2), c = 23.364(5) Å, V = 1797.2(6) Å3, Z = 4, R(F) = 0.039, and Rw(F) = 0.052. The two hydrochloride pseudopolymorphs were isostructural to the corresponding two hydrobromide analogues. Both hydrohalide hydrated crystals have a water molecule occupying a general position of symmetry, and another water molecule occupying a special position of C2-rotation symmetry. The hydrated hydrochloride salt also had an additional 0.322(17) partial occupancy water molecule (absent in the hydrobromide sesquihydrate) occupying another special position of C2-rotation symmetry, i.e., the extra water molecule occupied the special position in statistically ca. one-third of the unit-cells to give a total hydrate stoichiometry of 1.66 molecules of water. While the two hydrohalide anhydrates exhibited extended tropate ester conformations (phenyl-ring antiperiplanar to oxirane moiety) vs. compact conformations (phenyl-ring near the scopine underside) for the two hydrated hydrohalides, all four displayed other common structural features: axial N-methyl stereochemistry, antiperiplanar methylol oxygen/aromatic C(ipso) relationships, and phenyl-ring eclipsing of the C(alpha)-H bond. The CPMAS 13C NMR spectrum of (-)-scopolamine hydrobromide "trihydrate" shows it to be a conglomerate of (-)-scopolamine hydrobromide sesquihydrate plus two or more hydrated species (three ca. equal intensity carbonyl signals at 5.0 kHz spin-rate). High-speed rotor spinning (e.g., ca. 10 kHz and higher) causes a temperature-induced phase-transition to yield only the sesquihydrate form. The same transformation was noted with a 18 K rotor-temperature increase and an invariant 5.0 kHz spin-rate. The sesquihydrate spectrum remained after spin-rate decrease to 5.0 kHz, but the three component mixture 5.0 kHz spectrum was regenerated after three weeks sample storage within the capped rotor. The (-)-scopolamine free base crystalline melt CPMAS spectrum also shows a mixture of at least three hydrated species.Key words: stereochemistry, X-ray crystallography, solid-state NMR, CPMAS, anticholinergic.
The conformational preferences of N-methyl derivatives of the dopamine reuptake blocker threo-methylphenidate [Ritalin] and the p-methyl analogue were determined in the solid state and in solution and that of the erythro isomer in solution. The solid-state structures of (±)-threo-N-methyl-α-phenyl-2-piperidineacetic acid methyl ester hydrochloride [(±)-threo-N-methyl-methylphenidate hydrochloride] (2) and (±)-threo-N,p-dimethyl-α-phenyl-2-piperidineacetic acid methyl ester hydrochloride (5) were determined by single crystal X-ray diffraction analysis. (±)-2 underwent spontaneous resolution to give crystalline chiral plates containing two independent molecules in the asymmetric ring, and at each site there is a disorder involving the N-methylpiperidinyl ring methylene and methyl carbon atoms with a 0.710(7):0.290(7) ratio of occupancy factors. The two (2RS,3RS,4SR) major disordered molecules have similar structures consisting of a chair conformation for the piperidine ring with axial N-methyl and CH(Ph)COOMe groups. The two (2RS,3RS,4RS) minor molecules in the disorder also have similar structures and differ from the major ones by epimerization at nitrogen and inversion of the piperidine ring to afford an axial N-methyl group, and an equatorial CH(Ph)COOMe group. (±)-5 gave crystalline plates also containing diaxially disposed piperidinyl-ring substituents. Dissolution in D2O of either 2 or its erythro-epimer (3) each gives a 5:4 ratio of two species in which the major species exhibits an axial N-methyl group and an equatorial CH(Ph)COOMe group while the minor species has a diequatorial arrangement for both substituents. Both of the axial N-methyl threo or erythro major species in D2O are overwhelmingly conformationally biased in favor of an antiperiplanar H(2)···H(3) disposition and one piperidine ring invertomer. Dissolution of the threo or erythro epimers in CD2Cl2 gives the same axial N-methyl/equatorial CH(Ph)COOMe and diequatorially disposed species but now in a reversed ratio [respectively 3:20 for threo and 4:5 for erythro].
Cyclononanes from the 7 low-energy conformational archetypal families (twist-boat[bond]chair, twist-chair[bond]boat, twist-chair[bond]chair, twist-chair[bond]twist-chair, skew-chair[bond]boat, skew-chair[bond]chair, and skew-boat[bond]boat) were transformed into 12 of 13 MM3 stochastically generated cis-cyclononenes. This was done by systematically converting single bond synclinal endocyclic torsion angles, one-at-a-time, into double-bond synperiplanar analogues, followed by geometry optimization [e.g. density functional theory B3LYP/6-31G(d)]. Torsion angles adjacent to the new double bond maintained their signs, while their magnitudes usually changed considerably to accommodate the new neighboring synperiplanar torsion angles. The six remaining torsion angles all maintained their signs and approximate magnitudes compared to corresponding values in the seven saturated parent structures. As a result, the same "twist"/"skew" conformational descriptors previously used for the saturated conformers can now also be applied to the corresponding unsaturated analogues. Three conformational families have multiple members (subtypes) in which the double bond is located at different positions on the same ring conformation. The solid-state structures of (+/-)-1-phenyl-1,3,4,5,6,7-hexahydro-2,6-benzoxazonine-6-carbonitrile (22) and (1RS,3SR)-1-phenyl-3-methyl-1,3,4,5,6,7-hexahydro-2,6-benzoxazonine-6-carbonitrile (23) were determined by single-crystal X-ray diffraction analysis. The asymmetric unit of the Ponemacr; unit cell for 22 contains two symmetry-unrelated molecules, both of which exhibit a skew-chair-boat (SCBtype-2) conformation identical to that found for crystalline 23. This subtype has yet to be found in the Cambridge Crystallographic DataBase. Crystal lattice packing considerations alone cannot explain the observation of the SCBtype-2 conformation since (1)H NMR spectroscopy shows the same conformational bias when the crystals are dissolved in CDCl(3).
Crystalline (−)-scopolamine hydrohalide (bromide and chloride) salts exist in two conformational families for the tropate ester moiety: the compact conformation (hydrates, phenyl ring underneath the scopine moiety), and the extended conformation (anhydrates, phenyl ring ca. antiperiplanar to oxiranyl O-atom). CPMAS 13C NMR solid-state spectra of anhydrates and hydrates are different. In both tertiary and quaternary scopolammonium salts, phenyl rings are immobile in compact conformation crystals having ca. 2.5 Å close lateral neighbors on both faces of the planar moiety. Phenyl rings undergo a π-flip in extended conformation crystals having ca. 3.0 Å close lateral neighbors on either face of the aromatic plane. Due to different OC−Cα−CH2OH dihedral angles [synperiplanar (eclipsed, in compact) and (+)-synclinal (gauche, in extended)], the methylol carbon chemical shifts of crystalline tertiary and quaternary scopolammonium salts and analogues are diagnostic markers for the tropate ester solid-state conformation [δCH2OH downfield from alkoxy δC(3) for extended conformations and upfield of δC(3) in compact conformations]. These solid-state model Δδ relationships were used to deconvolute weighted time-averaged chemical shifts in different solvents: e.g., one axial N-methyl scopolammonium bromide phenyl-ring face is solvent exposed in the compact conformation predominating in D2O medium, while both faces are solvent accessible in the extended major conformational contributor in CD2Cl2 solution.
Nefopam methohalide (chloride, bromide, and iodide) medium-ring quaternary ammonium salts of the non-narcotic analgesic tertiary amine drug give crystals belonging to the identical monoclinic P2(1)/c space group, and all of these pseudopolymorphs exhibit the same packing motif. A singular boat-boat (BB) more compact conformation is observed in the nefopam methochloride crystal. Larger halide anions (bromide and iodide) increase the void distance between the 2(1)-screw axis related adjacent ammonium cations to accommodate void-size dependent equilibrium quantities of the twist-chair-chair (TCC) more extended conformation. The BB:TCC occupancy factors are 0.961(5):0.039(5) [193 K], 0.780(5):0.220(5) [293 K], and 0.755(6):0.245(6) [343 K] for the methobromide crystal, while values of 0.657(5):0.343(5) [193 K] and 0.592(7):0.408(7) [293 K] were measured for the methiodide. Above a minimum of ca. 2.53 A, the occupancy factors were found to be linearly correlated to the intermolecular (TCC)Me(eq)-H...H-Me(ax)(TCC) distance between abutting methyl group protons in 2(1)-screw axis related neighbors. Temperature-dependent occupancy factors for the two conformers are interpreted in terms of a medium ring atom-flip facile interconversion between the two low energy conformations in crystals containing the appropriate size intercation void. A BB/TCC atom-flip interconversion in the methochloride unit cell would result in van der Waals interactions due to an estimated 2.31 A close intermolecular (TCC)Me(eq)-H...H-Me(ax)(TCC) distance between adjacent 2(1)-screw symmetry ammonium cations. The 203 K low-temperature CPMAS 13C NMR spectrum of the methiodide salt showed two slow exchange limit (SEL) delta 57.91 [BB] and delta 63.10 [TCC] OCH2CH2N peaks. A variable low-temperature CPMAS NMR investigation of the solid methiodide showed complex dynamic behavior that cannot be interpreted solely on the basis of an atom-flip conformational interconversion. Local magnetic fields from the gem-dimethyl rapidly rotating proton magnetic dipoles provide a distance-dependent T1 relaxation mechanism for neighboring carbons in the solid-state.
Dissolution of brefeldin‐A in CDCl3 afforded two species in the ratio 13 : 1. Vicinal proton–proton coupling constants and NOE intensity enhancement measurements showed that the 13‐membered ring conformation found by x‐ray crystallography in the solid state appears to be preferred also in the solution‐state major species. The observance of signals from a solution‐state minor species (e.g. for the C‐15 methyl) shows that at least one other 13‐membered ring conformation exists in a small amount. While some degree of conformational flexibility for the major species cyclopentyl ring cannot be ruled out, the O‐13 hydroxyl group is clearly axially disposed in the solution state as it is in the crystal. Comparison of the solution‐state 13C NMR chemical shifts of the major species with those values measured by solid‐state cross‐polarization magic angle spinning show fairly good agreement with differences usually of 1 ppm, or less, with the exception of C‐2,8,6,11,15 signals where differences were ca 2–3 ppm. Copyright © 2000 John Wiley & Sons, Ltd.
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