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Classical writers depict Ptolemy as a drunken, debauched reveller, completely under the influence of his disreputable associates, among whom Sosibius was the most prominent. At their instigation, Ptolemy arranged the murder of his mother, uncle, and brother.

Following the defection of one of Ptolemy's best commanders, Egypt's Syro-Palestinian territory, Coele Syria, was seriously threatened by Antiochus III, the Syrian Seleucid ruler. In 219, when the Seleucid ruler captured some of the coastal cities, Sosibius and the Ptolemaic court entered into delaying negotiations with the enemy, while the Ptolemaic army was reorganized and intensively drilled. So grave was the threat that for the first time under the Ptolemaic regime native Egyptians were enrolled into the infantry and cavalry and trained in phalanx tactics. In 218 the negotiations collapsed, and Antiochus renewed his advance, overrunning Ptolemy's forward defenses. In the spring of 217, however, Ptolemy's new army met the Seleucid forces near Raphia in southern Palestine, and with the help of the Egyptian phalanx Ptolemy was victorious. Although holding the initiative, the Egyptian king, on Sosibius' advice, negotiated a peace, and the Seleucid army withdrew from Coele Syria.

After Raphia, Ptolemy married his sister, Arsinoe, who bore him a successor in 210. The Egyptians, however, sensing their power, rose in a rebellion that Polybius, the Greek historian, describes as guerrilla warfare. By 205 the revolt had spread to Upper Egypt.

To the south, Ptolemy maintained peaceful relations with the neighbouring kingdom. In the Aegean, he retained a number of islands, but, in spite of honours granted him, he refused to become embroiled in the wars of the Greek states. In Syria, also, Ptolemy avoided involvement in local struggles, though Sosibius attempted to embroil Egypt there. According to Polybius, Ptolemy's debauched and corrupt character, rather than his diplomatic acumen, kept him clear of foreign involvements. As his reign progressed he fell increasingly under the influence of his favourites, and around November 205 he died. His clique of favourites kept Ptolemy's death a secret, and about a year later murdered Queen Arsinoe, leaving the young successor at their mercy.